Endocrine Reviews December 2020: adrenal incidentaloma (IV)

This is the last post about adrenal incidentaloma. Here the original text, where everything is better explained, but it'll take you much longer to read.

SURGICAL INDICATIONS

• Every lesion >4 cm with indeterminate image characteristics should be excised because of risk of ACC
• Indeterminate lesions <4 cm should be discussed in MDT (multicisciplinar team) before surgical referral.
• Benign lesions >4 cm should be discussed in MDT before surgical referral, because the larger the image, the higher the ACC risk. There is no diameter cut-point for excision.
  
• Some clearly benign lesions like myelolipomas or cists may be referred to surgery if they cause compression simtoms or are very large. 
• Hypersecreting lesions (PhCC, Cushing, Conn) must be excised. 
• Adenomas with Autonomous Cortisol Secretion (ACS) must be discussed in MDT and in some cases surgery can be proposed depending on age, comorbidities, cortisol levels, and patient preferences.

 PERIOPERATIVE CARE

• Cushing's patients develop adrenal insufficiency after removal of adenoma, therefore they need peri- and postoperative stress glucocorticoid replacement and long-term therapy until a normal synacthen. 
• Pheochromocytoma must be pre-treated with alpha- and sometimes betablockers before surgery. After clamping tumor vascularity fluid and pressors may be needed to avoid hypotension. 
• Aldosterone-producing adenoma (APA) removal could lead to normalization of blood pressure, but not always. 

SURGICAL TECHNIQUES

• Laparoscopic transperitoneal adrenalectomy is the first-line procedure for benign lesions of small and medium size. 
• When open surgery is necessary, anterior, side or posterior approaches are available. 
• ACC can be laparoscopically accessed when <6 cm without evidence of extra-adrenal extension. Otherwise open surgery is preferred. When switch from laparoscopic to open surgery is needed, it should be done as soon as possible, before capsule is broken. 
• Laparoscopic posterior (retroperitoneoscopic) access has been recently developed. Trauma is smaller, but surgical field is also more restricted. 
• Robotic transretroperitoneal laparoscopic approach is possible. Range of motion and vision is better than in traditional surgery, but operative time and learning curves are longer. 

NONSURGICAL FOLLOW-UP

• Benign lesions <4 cm should not be followed-up, according to European reccomendations. AACE, however, recommends 5 y surveillance. 
• Attitud in benign images >4 cm must be individualized, ideally by MDTs. In younger patients, surgery is generally preferred and surveillance in older. In young patients when surgery is ruled out, MRI image is better to reduce radiation risk.
  
• Lesions >4 cm with indeterminate image are surgical. If for whatever reason it's not operated, 6-12 month image must be performed, and surgical referral indicated if diameters grow > 5 mm or size >20%. In case of smaller grouth, 6-12 month reassessment is adviced. 
• Repeated hormonal testing is not recommended if inicially normal. 
• In ACS, although risk of Cushing syndrome is negligible, annual hormonal testing can be performed

FUTURE RESEARCH

 Urine steroid metabolomics

• 24h urine steroids, including final products (aldosterone, cortisol, androgens) and its precursors can be analyzed using mass spectrometry (MS) using two techniques: Gas chromatography (GC-MS) or liquid chromatography (LC-MS/MS). 
• GC has got better resolution but is more cumbersome, therefore it's better for research. LC conversely is easier and more suitable for clinical use. 
• Inicially used for diagnosis of congenital metabolic diseases, with the aid of machine learning it can distinguish normal secretion from ACC secretion, because of elevated precursor pattern. ACC have elevated androgen precursor metabolites, sometimes associated to elevated GC or MC precursor metabolites. 
• Reaserch to identify patterns that distinguish ACC from ACAs are being developed and LC panels for use in clinical practice are appearing in the near future. 
  
• Aldosterone-Producing Adenomas (APAs) have also been found through metabolomics raised glucocorticoid precursor and cortisol metabolites. That is associated to signs of hypercortisolism in APAs (hyperinsulinism, IR) that resolves after adenomectomy. 

Functional imaging of adrenal cortex

• Iodocholesterol scintigraphy has been around since the 1970 using a cholesterol metabolite NP-59. Current SPECT-TC improved imaging has raised interest for this technique, particularly to differenciate APAs from hyperplasia in primary hyperaldosteronism (PHA). The problems are need for prolongued ACTH suppression, several-day imaging and high dose radiation. 
• Etomidate, a specific drug for CYP11B enzymes, has been radiolabelled to identify adrenal tissue in PHA. 11C, 18F and 123I have been used as isotopic labels. 123I has also therapeutical potential for ACC, although that requires validation. 

Functional imaging of adrenal medulla

• 123I MIBG has been used to identify chromafin imaging for 30 years, but it requires thyroid suppression and a 2-day procedure. Therefore, other tracers have been investigated, like radiolabelled DA, DOPA or ephedrine.  

Radiomics

• Research field consisting in extracting quantitative data from radiologic images like intensity, shape or texture. 
• It's been used to distinguish PhCC from adenomas in CT-indeterminate lesions, as well as ACC from ACAs.
• Using machine learning, quantified data extracted from texture images outperform experienced radiologist in differenciating benign adenomas from PhCC in indeterminate lesions, but clinical utility is not established.
  

Endocrine Reviews December 2020: adrenal incidentaloma (III)

...ADRENAL INCIDENTALOMA

This is the 3rd post about this issue. You can find the original article here and previous posts number 1 here and number 2 here .

 

 IMAGE WORK-UP

• All images > 10 mm must be evaluated for malignancy risk
• Clearly benign images like cysts or lipid-rich ones (myelolipomas) do not need further investigation.
• Size is clearly correlated to malignancy risk: 2% in <4 cm, 6% in 4-6 cm, 35% in >6 cm. 90% of cancers are > 4 cm. 
• Other characterystics are displayed by different radiologic techniques: 
• Unenhanced CT. First-line study. HU (arbitraty units of attenuation value, water being 0) <10 clearly suggests benign lesions. Care should be exercised in unhomogeneous images.
  
• Contrast-enhanced CT washout. 30% of adenomas are poor in lipids and have >10 HU, overlapping with PhCC and ACC. All three lesions take up contrast rapidly but adenomas show pronpt washout and the other not. Measurement at 1-2 min and 10-15 min washout rate may be calculated, being >60% suggestive of adenomas, but some PhCC can also wash out rapidly. 
• Dual Energy CT. It can provide additional information about composition of images, but further research is needed to estimate its role in AI evaluation.
  
• MRI with chemical shift (in-phase/out of phase). Very useful in assessing lipid content. Could be first-line study in children or pregnant. If an AI is discovered by a MRI and is clearly lipid-rich, no further studies are neccesary.
  
• PET/CT has sensitivity and specificity of 90%, false-negatives in small or nod FDG-avid metastases, false-positives in metabolicaly active adenomas and PhCC. More useful to rule-out metastases in patients with known cancers or previous to surgery. 

FOLLOW-UP

• No need to follow up images <4 cm with benign characterystics
• Benign images >4 cm: image reassessment in 6-12 months. 
• Discuss in multidisciplinary team (MDT) with endocrinologists, surgeons, pathologist, radiologist, nuclear medicin specialists, when:
• no clear benign image
• growth in follow up
• hypersecretion (mostly ACS, view post 2)
• considering surgery

BILATERAL AI

• Initial considerations
• Both masses must not be the same, if hypersecretion, maybe only one is secreting. 
• Always consider adrenal insufficiency, mostly in metastases and hemorrhages. 
• Autonomous Cortisol Secretion (ACS)
• ACS is twice as frequent (35 vs 18%) in bilateral adrenal enlargement
  
• Primary Bilateral Macronoduar Adrenal Hyperplasia (PBMAH) should be suspected in ACS + bilaterality. Etiology: aberrant G protein coupled receptors, not for ACTH, but able to activate downstream pathways
• Unenhanced CT may or not show nodules. When present, nodules may have >10 HU and be positive on PET. Be careful!
• Surgery is recommended in PBMAH + ACS when UFC >3xnormal range. Bilateral excision is indicated in symmetrical enlargements. In selected cases with asymmetry unilateral adrenalectomy may be performed, but although initial remission is high (85%), long-term results are poor (30%). 
  
• Congenital Adrenal Hyperplasia (CAH). Rare in adults, suspect only when elevated ACTH. Suppresed ACTH suggests malignancy or PBMAH even if elevated 17OH prog.
• Pheochromocytoma. 10% are bilateral, mostly in genetic syndromes. 
• Metastases. 
• 75% of patients with known malignancy and AI have methastases, the other 25% are primary adrenal lesions. 
• Adrenal insufficiency is rare even in bilateral metastases but must always be evaluated. 

BIOPSY

• Generally not indicated for three reasons:
• No able to differenciate adrenal adenoma and carcinoma.
• Risky if pheochromocytoma.
• Seeding adrenal cancer
• If known malignancy and suspected metastases that would affect management biopsy is indicated in selected cases. 

Next post: surgery, nonsurgical follow-up, and future research. 

Endocrine Reviews December 2020: adrenal incidentaloma (II)

Click here to find the original article with lots of wonderful pictures and a PDF to print.

ETIOLOGY AND CLINICAL PRESENTATION

• Adrenocortical adenoma (ACA). Mostlly nonsecretory, can produce ACTH independent cortisol or angiotensin independent aldosterone, more rarely, androgens or estrogens. Activation of cAMP-PKA, a downstream mediator of ACTH-G protein receptor pathway, is implicated in its pathogenesis. 
• Cortisol-producing adenoma. Clinically variable. Usually ACTH-independent, sometimes G-protein receptor hyperfunction. 
• Adrenocortical carcinoma (ACC). 
• Rare, 1-2 /M/y. Peak age <5 and 40-60.
• Most sporadic. Genetic syndromes Li-Fraumeni (p53), MEN-1, Beckwith-Weidemann.
  
• 60% producers, 45% cortisol, half of them cortisol + androgens, 10% only androgens, <10% estrogens. 
• 90% >4 cm
• 30% painful
• Mutations: beta-catenin leads to Wnt activation, GNAS gene mutation with Gs-alpha activation, and mutations affecting PKA: inhibition of regulatory subunit or activation of catalytic. 
• Aldosterone-producing adenoma (APA) has mutations in K channel KCNJ5 in 40%. 
• Bilateral nodules 10-15%. Most frequent metastasis, bilateral adenomas and primary bilateral macronodular adrenal hyperplasia (mutations in armadillo repeat containing 5 ARMC5), it can also be congenital adrenal hyperplasia, cushing's disease, ectopic ACTH, or bilateral pheochromocytoma. 
• Pheochromocytoma.
• 0,8/100,000 /y
• 40% germline mutation, mostly SDHB, SDHD, NF1, RET (MEN2), VHL
• Sporadics: 2 types of mutations:
• Cluster A (hypoxia): SDH D, C, B, A, AF2, VHL and other. Usually extra-adrenal
• Cluster B (protein-kinases): NF1, RET, other. Mostly adrenal. 
• NF1 and RET secrete more metanephrine, VHL and SDH more normetanephrine, VHL more methoxythyramine than SDH.

ENDOCRINE HYPERSECRETION EVALUATION 

• Pheochromocytoma screening
• 90% hypertension, 90% headache, 50% sweating+headache+tachycardia
• 99% >10 HU on TC
• Screening recommended in all cases: plasma or 24h urinary metanephrines (LC MS/MS)
  
• Autonomous cortisol secretion (ACS)
• Frequently asymptomatic. For overt Cushing, recommended diagnostic tests are 24h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and 9h cortisol after 1 mg dexamethasone.
• ACS is a- or oligosymptimatic.
• Up to 20% of all AI.
• Associated to hypertension, diabetes, insulinresistance, obesity, and increased mortality. 
• No gold-Standard, screening usually 1 mg DXM, <1.8 mcg/dL excludes ACS, 1.9-5 is suspicious, and >5 confirmatory. 
• UFC has lower sensitivities 30-75%, and LNSC has mixed results for ACS.
• Clinical consequences:
• Hypertension is present in 40-90%
• Diabetes or prediabetes 10-70%
• CV events and mortality are clearly increased. 
• Effect on bone are not so clear. Both trabecular and cortical bone loss as well as vertabral fractures are reported. 
• Consequences of reversal
• No RCT have shown benefits from adrenalectomy in ACS (there are ongoing)
• As surgery is a risky procedure, recommendation is control of CV risk factors. 
• Natural history
• Non-secreting adenomas NSA rarely develop ACS (5%)
• Both clinical Cushing and spontaneous regression are exceptional in ACS <0.1%
  
• CV risk factors increase prevalence in ACS more than in NSA 
• Mortality was similar in ACS than in NSA (meta-analysis) (contradicting previous statements of this post). 
• Recommendation is no follow-up in NSA and 5y follow up in ACS.
  
• Aldosterone secretion
• Current recommendation is measuring A/R ratios in case of hypertension or hypokalemia
• There may be subclinical suppressed renin cases who would develop future hypertension, but there are no clear data so far. 
• Sex hormones
• Isolated estrogen or androgen secretion are very infrequent in adenomas and should raise suspiction for ACC.

 That´s all for today, in next post imaging evaluation. 

Endocrine Reviews December 2020: adrenal incidentaloma (I)

There is an extense review about adrenal incidentaloma (AI) for the dec-2020 number, although the paper was from April. It's more than 40 pdf pages, so it'll be reviewed in a few posts. here the first. Original article here. 

Key points:

• It affects 2% of populations, 7% in >70 and rare <40. 
• 2% are malignant and 10% have hypersecretion. 
• Autonomous cortisol secretion and pheochromocytoma must always be excluded. Aldosterone secretion only when hypertension or hypokalemia. 
• Unenhanced TC is the inicial test of choice. 
• Once malignancy is excluded the patient can be discharged. 
• Careful evaluation of clinical impact before recommending surgery should be exercised in case of cortisol hypersecretion. 

EPIDEMIOLOGY

• Prevalence varies, 1-7%, raising with age, peaking 50-70. 
  
• It is rare in <30, in these cases it must always be investigated to exclude malignancy or hypersecretion. 
• No clear gender predominance. 
• Mean size 30 mm, those <10 mm must not be further investigated unless clinical suspition. 
• Size >40 mm increases cancer risk. 
• No clear lateralization.
  

 ANATOMY

• Adrenal cortex comes from mesoderm (urogenital ridge) and medulla from ectoderm (neural crest). 
• SF1 (NR5A1) is a key factor for cortex development. By 3 years of age 3 layers are developed (glomerulosa, fasciculata, reticular)
• Adrenals weigh 4 grams, 5x2x1 cm and are extensively irrigated.

PHYSIOLOGY

• Glomerulosa zone secretes 100-200 mcg/d of aldosterone thanks to CYP11B2 enzyme. 
• Fasciculata zone secretes 10-20 mg/d of cortisol due to CYP11B1.
• Regulation and hormonal actions are beyond this review's scope. 
• Catecholamines derive from tyroxine (TH) → L-DOPA (AADC) → DA (DBH)→ NA (FNMT) → A. FNMT is only in adrenal medulla, NA is also syntetized in sympathetic ganglia and paraganglia. 
• CA metabolism is varied, NA is deaminated bt MAO to 34 DHPG and by COMT to o-metilated metabolite NMN, A through COMT to MN and DA to methoxythyramine. In pheochromocytoma, 90% of CA are metabolized in the tumor by COMT to o-metilated metabolites MN and NMN. Therefore, these molecules are more reliable tumor markers than A or NA. 

HYSTOLOGY.

• Tumors from adrenal medulla are positive to S100 and chromogranin. 
• Cortical origin tumors express cytokeratin, alpha inhibin, calretinin and SF1.
• Adrenocortical cancers are positiv for melan A but, unlike melanomas, negative for S100.
• Weiss score >3 is helpful to differentiate adrenal adenoma and carcinoma, and Ki67 is also indicative of aggressive behaviour. 
• PASS (pheochromocytoma of de adrenal gland scaling score) and GAPP (grading of the adrenal pheochromocytoma and paraganglioma) are scores to label pheochromocytomas al benign or malignant.
  

 

ADA Standards 2020: insulin delivery, pumps, sensors and internet.

 INSULIN INYECTIONS

• Both syringes and pens (combining syringe, vial and button) can be used to deliver insulin, depending on patient's preference, insulin type and dosing, and costs. Inhaled insulin is also available.
  
• For people unable to properly self-inject insulin because of dexterity or visual issues, pens with aids can be helpful.
• Needle gauges from 22 (broader) to 33 (thinner) are available, being thinner less painful.
• Needle lengths from 4 to 12 mm are available, shorter lengths reduce risk of IM deposit.
  
• Injection or infusion sites must be checked at least annually.
• Smart pens and dose calculator help the patient in some cases.
• In-patients must be allowed, when possible, to self-administrate their insulin. 

INSULIN PUMPS

• Pumps should be offered to any adult, child or adolescent with type 1 diabetes who is able to safely manage the divice.

Pumps (CSII) have been around for more than 40 years. Studies comparing them to MDII are short and small. Meta-analysis show small advantages of  CSII in terms of A1c (0,3%) and severe hypoglycemia. 

Problems with pumps are related to infusion set (risk of DKA) or skin (infection, lipohypertrophy or atrophy.

Little data compare CSII and MDI in children, RCT are difficult because of financial issues, rapid change of technology that renders old devices obsolete, and lack of blinding. It is possible that it slightly lowers A1c and DKA risk. There are no data in teenagers. 

Some patient with other types of diabetes, like long-term type 2 diabetes, pancreatectomized, or cystic fibrosis-related, as well as older patients with T1DM, may benefit from CSII in selected cases. 

PUMP AND SENSOR COMBINATION

• Sensor-augmented pumps with low glucose suspend can help adults and children with T1DM reduce hypoglycemia. These devices can be considered in case of frequent nocturnal hypoglycemia.
  
• Automated insulin delivery systems may be considered in children (B) and adults (A) to improve glycemic control. Currently these devices are hybrid closed-loop systems, where basal insulin infusion rate is controlled by an algorithm that receives continuous imputs from the sensor, but bolus must be manually added. They can reduce exercise-induced hypoglucemia and have psychological benefits. Here the result of a 6-month-trial that caused an update in ADA Standard in june, where closed-loop systems outperformed sensor-augmented pumps in TIR and rest of ranges. 

• DIY devices cannot be prescribed by health providers, but they can provide safety information and backup stategies. 

DIABETES AND INTERNET

• Patients seek more and more medical advice in the internet. This activity is not regulated and many apps and websites have been manufactured by people with low expertise in diabetes. 
• Data collection and storage poses security and privacy problems. 
• Despite lack of scientific evidence, many apps help people with diabetes and prediabetes lose weight and control their glycemia, therefore they can be a reasonable choice on an individual basis.
  

Diabetes Care Sept-20

Marit de Jong et al used UK biobank to study MI events in people with and without diabetes and study the differences by gender and A1c level. They saw that MI was more frequent in men both in diabetes and people without it, but that diabetes raised risk more in women. A1c was also clearly associated with MI, increasing 18% risk for every 1% A1c. 

A review from Giulia Ferrannini about cardiovascular risk in diabetes. 4785 words just to smach our brains with 3 basic ideas : 1.- people with CV events frequently have hyperglycemia; 2.- those people usually have worse prognosis and many and undiagnosed or insufficiently treated; 3.- we've got newer (and expensive) drugs that have showed CV reduction in this population. In my opinion it's just part of the campaign advocating for cardiologist to detect and treat diabetes with SGLT2-i and GLP-RAs. The abuse of terms like "disglycemia" and "holistic" and the use of graphs like this:

...made it hard for me to finish the article without nauseating.

Acarbose Cardiovascular evaluation (ACE) trial was conducted in China and included 6000 individuals with prediabetes (IGT) and CHD. Randomized to acarbose or placebo, the researchers saw that Acarbose reduced diabetes incidence, but just 18%. It also contributed to regression to normoglycemia, but just 16%. More important would have been to know if it lowered Cv events, but that's not mentioned.

Which GLP-1 RAs are better when associated to insulin, short-acting or long-acting? That's what Jessica Huthmacher and colleagues wanted to know. They meta-analyzed 14 RCT and found that long-acting (lira-, dula-, weekly exe-, semaglutide) drugs were better than short ones (lixi and exenatide twice daily) in terms of A1c, weight and hypoglycemia. By the way, severe hypo was similar in both groups. 

In USA, people at risk for diabetes enrolled in CDC's Diabetes Prevention Recognition Program (diet and exercise basically). Cannon et al wanted to know factors associated to adherence to it and saw that, at week 17, older and white people (what they understand for white, i.e. not me for instance) dropped less than black, hispanics and youngs. 

In "Perspectives of Care", Davidson advocates for not using metformin in prediabetes, because 2/3 will never develop diabetes, 1/3 spontaneously return to normal glycemia, and none of them have microvascular risk. 

In commentaries, Marx from Germany comments on the implications of shifting every eligible patient with T2DM to newer drugs with CV benefits. Even if in the long run (assuming you believe results from trials will translate to clinical practice) it were cost-effective, initial costs woult be gigantic, difficult to assume for any health system. Discussion is served.

Ahead of print:

• Duration-8 randomly assigned dapaglyflozin, weeekly exenatide or both to T2DM patients on metformin with A1c >8%. It took 2 years and was completed only by 60%. Dual treatment reduced A1c in 1,7%, exenatide 1,29% and dapa 1,09%. 
• Unsworth reported increased incidence of type 1 diabetes during covid pandemics, but only a minority had PCR or Ab evidence of SARS-COV-2 infection and absolute number was low, so it can be  a random event. 
• Real-time CGM underestimates hypoglycemia in hyperinsulinemic hypoglycemic clamp, compared to standard blood glucose meters.
  

There are many more articles that I've no space to comment but you will find all them by clicking here.

ADA Standards 2020: Diabetes Technology: SMBG and CGM.

 SELF-MONITORING OF BLOOD GLUCOSE (SMBG)

• In type 1 diabetes A1c and number of SMBG are correlated. In children and teenagers, -0.2% for every daily test.
  
• Patients in intensive insulin regimes should use SMBG:
• Before meals and snacks
• At bedtime
• Before exercise
  
• When hypos are suspected
• After hypos until normal range is achieved
• Before and during critical activities like driving
• In patients in less intensive insulin regimes, SMBG as part of DSMES programs help guiding treatment and self-management. 
• In patients not taken insulin SMBG has not proven A1c reductions, it may (level evidence E) help when changing diet, physical activity or drugs to evaluate response. 
• Proper technique, validated devices and strips, and knowledge about interfering factors like high vitamin C levels or hypoxemia are neccesary to use SMBG:
  
• Glucose oxidase methods give falsely low levels in high oxygen tensions, like O2-therapy, and falsely high in low OT, like hypoxia or venous blood. 
• Glucose oxidase methods show interference with frequently used substances like acetaminophen or ascorbic acid.
  

CONTINUOUS GLUCOSE MONITORING (CGM) DEVICES

Apart for blinded or professional-used devices, there are two types ot technologies: real-time (they both measure glucose and deliver data to device continuously) and intermitently scanned CGM (they measure glucose continuously but deliver data only when put in contact to a device). They can be used without calibration with SMBG.

• High level of DSMES (including SMBG technique) is neccessary for the patient to profit from this techlology. 
• In adults with type 1 diabetes, both real-time and intermitent CGM are useful to reduce A1c and hypo rates, particularly in patients with A1c>target, hypoglycemia unawareness (HU) or frequent hypos, although there ar more studies for real-time devices. A1c reductions are about 0,5%, and new intermitent devices with alarms are not mentioned in this section. 

• In type 2 diabetes on insulin with A1c>target, real-time CGM is useful to lower A1c and hypoglycemia. In T2DM on oral agents, whether or not with insulin, hypoglucemia does not improve. Intermitent devices showed contradictory results in T2DM.
  
• Consider CGM in children and adolescents with T1DM to improve glucose control, althoug benefits correlate with adherence. In this age group evidence is poorer. A1c may improve only when device is used at least 6 days per week, data on hypoglycemia are scant, and in intermitent CGM there are only observational studies.
  
• Real-time CGM should be used as close to daily as possible, and intermitent CGM should be scanned at least every 8 hours. 
• In pregnant women with T1DM, real-time CGM is useful to improve A1c, TIR and neonatal outcomes. 
• Side effects of CGM devices are contact dermatitis, sometimes associated to isobornyl acrylate, a skin sensitizer. 
  

ADA Standards 2020: Glycemic targets

 

If you've got plenty of time, you'll find this section much better explained here. But please, trust me, in 3-5 minutes you'll find the gist of it reading this post. 

HBA1C

• ADA recommends, with no scientific evidence whatsoever, to perform A1c every 6 months if glycemic targets (see later) are met, or every 3 if not. 
• A1c could be (not clear) a little higher in people of African origin. Some genetic variants could lead to lower values, like HbS (-0.3%) or GDPDH deficiency (-0.8%).
• A1c(%)-SMBG (mg/dL) correlations are: 5-97, 6-126, 7-154, 8-183, 9-212, 10-240, 11-269. They're easy to memorize and very useful in clinical practice. 

GLYCEMIA

• Self-monitored blood glycemia (SMBG) and continued glucose monitoring (CGM) are key for diabetes control. It helps evaluating efficacy of therapies and lifestyle, like foods, physical activities, and other. 
• CGM results must be presented in a validated and standarized way that includes:
• Number of evaluated days (recommended >=14)
• % time device is measuring (rec. >70%)
• Mean glycemia
• Variability (rec. <36%)
• GMI Glucose Management Indicator
• % time >250 mg/dL (Time Above Range TAR level 2)
• % time >180 mg/dL (Time Above Range TAR level 1)
• % time 70-180 mg/dL (Time in Range TIR)
• % time <70 mg/dL (Time Below Range TBR level 1)
• % time <54 mg/dL (Time Below Range TAR level 2)

 A1C AND GLYCEMIC GOALS

Leaving apart pregnants, older adults and children and adolescents, main goals are:

• <7% as a general rule. That means pre-prandial values of 80-130 and peak post-prandial <180 mg/dL. Before 2015 pre-prandial suggested values were 70-130.
  
• <6,5% if can be achieved safely, without hypogluycemia or adverse effects
• <8% in these cases:
• History of severe hypoglycemia
• Limited life expectancy
• Advanced micro or macrovascular complications

Rationale:

Microvascular complications

• DCCT, Kumamoto and UKPDS trial showed that lowering A1c is associated to reduction of microvascular disease, particularly at high A1c levels. 
• Reducing A1c <7% is also beneficial as to microangiopathy, but not so much, and sometimes at the expense of hypoglycemia (T1D) or polypharmacy (T2D), and is only cost-effective if can be safely achieved. 
• In diabetes >10 years with macrovascular disease, ACCORD, VADT and ADVANCE trials showed that microvascular benefits of lowering A1c <7% do not make up for mortality costs and is not recommended. 
  

Macrovascular disease

• In T1D (DCCT), as well asrecently diagnosed T2D (UKPDS), A1c reduction lead to CVD event reduction. 
• In advanced T2D, A1c reduction does not reduce CVD nor mortality. Hypoglycemia must be avoided, and GLP-RAs and SGLT2-1 are recommended in established CVD because they reduce CV events and mortality. 

Postprandial glycemia 

• Although post-prandial peak is correlated to CV disease, intervention studies have not showed that its reduction has CV benefits beyond A1c reduction
• The closer to 7% A1c is, the highest contribution postprandial glycemia has. So, in cases with A1c around 7%, to improve control, focus in reducing PP glucose. 

HYPOGLYCEMIA 

• Hypoglycemia is classified in 3 levels:
• Level 1: <70 mg/dL, it is the level for contrarregulatory response
  
• Level 2: <54 mg/dL, it is the level for neuroglycopenia. Asymptomatic level 2 hypoglucemia strongly suggests HU (failure of contraregulatory and autonomic response).
  
• Level 3: need assistance irrespective of glycemia. 
• Fasting, delayed meals, alcohol, exercise, and sleep are precipitants for hypos.
  
• Patients at risk for hypo (insulina, secretagogues) should be screened for hypoglycemia unawareness (HU)
• Glucagon must be prescribed for patiens at risk for level 2 (severe) hypoglycemia. Apart from glucagon powder, intranasal and SC solutions have been recently approved by FDA.
  
• Patients with history of level 3 hypo, HU or several level 2 hypos should relax A1c for several weeks to avoid HU. 
• Patients with cognitive impairment must be screened for hypoglycemia and monitored for cognitive progression. In older subjects with DM, level 3 hypoglycemia is associated with CogImp, but not in DCCT population: Causal relation is not clear.
  
• Concious patients with glycemia <70 mg/dL must be treated with 15-20 g of oral glucose, although other glucose-containing CH are also useful, although not protein-rich food in type 2 diabetes because it raises insulin secretion. In any case, glycemia should be monitored in 15 min, and treatment repeated if not resolved. after resolution, eat a snack. 
• Hypoglycemia training programs must be provided to patients with level 3 hypo or HU. 
• In T1D, Real-Time CGM reduces time spent in range 54-70 mg/dL (level 1 hypo) but not in level 3. Little data are for flash devices and for type  2 diabetes. 

INTERCURRENT ILLNESS

• Acute events like illness, surgery, trauma, raise glycemia and may precipitate DKA or NHH.
• Glycemia and, if indicated, ketonemia must be frequently measured
• Glycemia correction, usually with insulin, even in non-insulin dependent individuals, as well as adequate nutrition and hydration, is neccesary. 
• Hospitalization for acute illness is more frequent in diabetes than in individuals without it. For correct in-hospital care see here.
  

ADA Standards 2020: Psychosocial issues and smoking.

PSYCHOSOCIAL ISSUES

Introduction 

• Psychosocial screening should include:
• Attitudes towards diabetes and treatment
• Mood
• General and diabetes-related QoL
• Financial, social and emotional resources
• Psychiatric history
• Standarized and validated tools should be used to detect: diabetes distress, anxiety, depression, disordered eating, and cognitive capacities. 
• Patients >=65 can be screened for depression and cognitive impairment.
  

Diabetes distress

• Dfn: negative psychological reactions related to having to manage diabetes. It's mostly related to burdens of diabetes management, disease progression and complications.
  
• Affects about 45% of patients
• Should be screened with "validated tools" like PAID (problem Areas in Diabetes) or DDS (Diabetes Distress Scale), see diabetesdistress.org
  
• If positive, referred to a DSMES provider, given the fact that DSMES improves it
• If DD negatively affects diabetes management, to a mental health specialist with knowledge in diabetes.
  

Anxiety

• Screen for anxiety disorders AD in people who show symptoms of anxiety including hypoglycemia unawareness with fear of hypoglycemia
• Refer to mental health if positive screening.
• AD affect 19.5% of people with diabetes. The most common causes are hypoglycemia, not meeting glycemic targets, injections, and diabetes complications.
• Obsessive-compulsive disorder should be suspected in cases off attitudes toward self-management that go far beyond the usual care. 
• Structured programs of Blood Glucose Awareness Training (BGAT) help improving glycemic control and hypoglycemia en cases of fear of hypoglycemia and hypo unawareness. BGAT are usually 8 weekly sessions in groups of 5-15 subjects.
  

Depression

• It affects 25% of type 1 or type 2 diabetes. It should be yearly screened with validated measures
• If positive screening, refer to a MH provider, its treatment improves diabetic outcomes. 
• If depression improves, reconsider therapy, previously rejected measures like physical activity or intensive insulin regimes can be accepted now.
  

Disordered eating behaviour

• The most DEBs are insulin omission in type 1 diabetes and binge eating in type 2 diabetes. 
• Suspect DEB in cases of unexplained worsening of glycemic control and weight lose
• Certaing drugs like GLP-1 RA may help reducing hunger in binge-eaters.
  

Serious mental illness

• Schizophrenia and other serious mental illness increase the risk for diabetes and it should be routinely monitored
• Atypical or second-generation antopsychotic drugs like olanzapine particularly raise diabetes risk 
• Because of difficulties in self-management, a caretaker must be included in the decision-making process and diabetes treatment plan. 

SMOKING AND DIABETES

• Advise all smokers with diabetes not to smoke or use e-cigarettes. Evedence suggests short advice against smoking is effective. In motivated patients, pharmachologic treatment is also beneficial. E-cigarettes are also harmful and not advisable.
  

 

ADA Standards 2020: Physical Activity Recommendations.

Proven benefits of physical activity in diabetes are:

• Improvement in glycemic control 
• Reduction of CV risk factors and CV mortality
• Contribution to weight lose
• Inprovement of well-being

In spite of that, less than 50% of patients meet the recommended goals Current ADA recommendations as to exercise and diabetes are:

For children and teenagers with type 1 or type 2 diabetes:

• >=60 min/d of moderate or vigorous exercise

 and

• >= 3 days/week of muscle-strengthening or bone-strenthening activities

For adults with type 1 or type 2 diabetes:

• One of them:
• >=150 min of moderate to vigorous-intensity aerobic activity, at least 3 days a week, with no more  than 2 days without exercise, that is, mon-wed-fri, tue-thu-sat, etc. 

or

• >=75 min/week of vigorous-intensity or training intervals for younger and more physically fit adults, defined as those able to run at least 10 Km/h (6 miles/h) or 6 min/Km.
  

and

• 2-3 sessions/week of non-consecutive days of resistance exercise (free weights or weight machines), because clinical trials have proven benefit of it in A1c.
  

and

• Decrease the amount of time spent in sedentary activities, interrupting prolonged sitting every 30 minutes

For older individuals:

• Flexibility and balance training 2-3 times/week, including yoga and tai-chi based in patient preferences.

PRE-EXERCISE EVALUATION

• Coronary artery disease screening for asymptomatic individuals is not recommended, but caution should be exercised in patient with risk factors
• Non-physically fit and high risk individuals should begin with low-intensity and short-duration sessions
• Conditions that contraindicate certain exercises are:
• Uncontrolled hypertension. In diabetic kidney disease, however, although vigorous exercise raises albumin excretion, there is no acceleration of kidney failure and exercise is not contraindicated.
  
• Untreated proliferative retinopathy: vigorous-intensity aerobic and resistance exercise is contraindicated because of risk of retinal detechment or vitreous hemorrhage
  
• Autonomic neuropathy. They can develop exercise hypotension, poor visual night adaptation, thermoregulatory failure, and cardiac arrest. Therefore they should undergo previous cardiac evaluation.
  
• Peripheral neuropathy: they must wear propper shoes and protections to avoid skin wounds, ulcers and charcot foot. Brisk walking is not contraindicated in this case
  
• Previous foot ulcers or charcot foot

EXERCISE HYPOGLYCEMIA

• Patients on insulin or secretagogues must be trained to recognize exercise and post-exercise hypoglycemia, and check their glycemia before, during and after the exercise. Hypoglycemia may occur depending on some of those factors:
• Duration and intensity of exercise
• Insulin or secretagogue dose
• Pre-exercise glycemia
• Previous ingested carbs
• Patients not on insulin or secretagogues are at low risk of hypoglycemia. 
  

ADA Standards 2020: Nutritional Therapy

This post is about the most recent scientific evidence translated to recommendatios about what to eat in diabetes. As usual, better and more extensively explained you can find it here. 

 According to the ADA, all individuals with DM should be referred for individualized MNT provided by a registered dietitian nutritionist (RD/RDN) who is knowledgeable and skilled in providing diabetes-specific MNT (56) at diagnosis and as needed throughout the life span, similar to DSMES. MNT reduces A1c 1-1,9% in type 1 diabetes and 0,3-2% in type 2 diabetes. 

Well, that's another pending subject in my clinical setting. Dietary advice in my hospital is delivered by the nurse educator, as part of DSMES program (see previous post about DSMES). No registered dietitian or nutritionist gives regular and structured dietary advice to diabetic patients at all, not only in my hospital, but in every hospital i know. I don't know, and haven't been able to find, how many patients with diabetes receive MNT from a registered dietitian.

Goals of nutrition therapy are attainment of desired weight, A1c, lipids and blood pressure according to management plan, and delay or prevent diabetic complications. It should be individualized, that is, having into account patient preferences, social background, food availability, and beliefs, restricting types or amounts of foods only when indicated by scientific evidence. 

Different types of macronutrient distribution are acceptable, so the one that fits patient characteristics must be chosen. Mediterranean diet, vegan diet, or low-carb diet are examples of suitable meal plans. 

WEIGHT MANAGEMENT

• Lifestyle  modifications for all individuals with DM and overweight/obesity to achieve and attain 5% weight lose is  recommended. A1c, lipids and BP benefit from 5% weight lose in most of these cases, althoug a larger weight reduction is associated to better outcomes.
  

CARBOHYDRATES

• CH sources should be minimally processed and high in fiber. Nonstarchy vegetables, fruits, dairy products, whole grains, and minimal added sugar is recommended.  
• Reduced overall CH amount has the most evidence to improve glycemic control and can be applied to different eating patterns. 
• In individuals with flexible insulin regimens, carbo counting to calculate meal insulin dosing is recommended, as well as, with lower level of evidence, fat and protein counting. 
• On fixed insulin doses, adapt carb amount and timing to insulin action to reduce hypoglucemia and hyperglycemia. 
• Both in diabetes and prediabetes, replace sugar-sweetened drinks with water to improve glycemia, weight, CV risk and fatty liver.
  

PROTEIN

• In type 2 diabetes, proteins increase insulin response to CH, so avoid foods rich in CH and proteins when treating hypoglycemia.
  

DIETARY FAT

• Mediterranean eating plan high in mono- and polyunsaturated fat improves glycemia and CV risk. 
• Foods rich in n-3 fat like fish (eicosapentaenoic EPA, docosahexaenoic DHA) or nuts and seeds (alpha-linolenic ALA) reduce CV risk, but n-3 supplements are not recommended because evidence does not support a beneficial role. 
• As to saturated, trans fat and cholesterol, follow recommendations for general population.
  

MICRONUTRIENTS

• In absence of documented deficiency, micronutrient, vitamins, herbs and other dietary supplements have no benefit in diabetes or CV disease.
  

ALCOHOL

•  Alcohol consumers must do it in minimal quantities: one or two daily drinks in women and men respectively. 
• Alcohol is associated to hypoglycemia, delayed hypoglycemia, weight gain and hyperglycemia.
  

SODIUM

• As for general population, limit sodium to <2.3 g daily. 
  

NONCALORIC SWEETENERS

• They can reduce CH and total energy load if not replaced with other caloric foods, but water is better. For those used to sugar-sweetened drinks, they could be a short-term alternative, but again water is better.
  

Diabetes Education in ADA Standards 2020: Diabetes Self-Monitor Education and Support.

There is no doubt that Diabetes Education, or the way it's now called, Diabetes Self-Monitor Education and Support (DSMES), is the central part of any diabetes treatment program. In this post we're going to explain what it is, who can be providing it, when, how, and which benefits can be achieved with it, and which difficulties it has to be implemented

What is it? It's the knowledge (information, attitudes, skills) that every individual with diabetes must have in order to properly manage their disease. It includes general information about what diabetes is, its consequences, its causes, symptoms, short- and long-term complications, as well as the effect of the treatment including adverse effects and hypoglycemia. Information about healthy and recommended nutrition (carbs, fat, proteins etc) and physical activity to manage the disease also belong to DSMES. Skills like how to properly inject insulin or measure glycemia on a fingerstick, continuous glucose monitoring or, if necessary, insulin pumps are of course part of it.

Who provides it? Nurses, dietitians and pharmacist have proven to effectively provide DSMES. There are platforms to get certitications as diabetes educator, like www.ncbde.org or www.diabeteseducator.org.

When should it be provided? There are, according to ADA, four moments in the disease that are particularly important:

• At diagnosis
• Annually
• When complications occur
• At transitions i.e. change of doctor.

How can it be delivered to the patient? There are three different modalities to provide DSMES: individual face-to-face, in groups face-to-face, or online. All three modalities have proven to be effective, although there are intrinsic differences. Individual modality can be more patient-centered, but online strategies may reach a bigger number of patients.

Benefits. DSMES not only improves diabete knowledge and self care, it also lowers A1c, weight, improves QoL, reduces all-cause mortality and health costs. If you don't believe it, click here.

Despite all those benefits, only 5-7% of individuals eligible for DSMES in the US trough Medicare or a private insurance plan actually receive it. How is it possible that the stem of the  tree, the center, the nucleus of treatment and management of diabetes is only performed by 5-7%? Can't believe it!!

I've searched the conditions for Medicare reimbursement for example (click here). Someone with diabetes with Medicare in the US has the right to an initial DSMT of 10 hours to be provided in a 12 month period, the first of which can be individual and the other 9 preferable in group, unless certain conditions are met (no groups available, communication barriers or insulin treatment and unmet skills, certified by a doctor). After that initial 10 hours, there is a 2h/year DSMT follow-up. Online education is not reimbursed.

In my country, Spain, where the vast majority of people with diabetes are treated by the public health service, DSMES includes, at least in my experience, much more patients that this 5-7% of diabetic population, although most of them do not reach by far those 10 hours the first year or 2 hours the following ones. The public policy is clearly to reach more people at the expense of incomplete DE programs. 

All this reveals how difficult it is to provide proper DSMES to all diabetic individuals, and it's clearly apending subject for any health system.

Comprehensive Medical Evaluation and Assessment of Comorbidities II: Standards of Medical Care in Diabetes—2020

Here the second part about the rest of the chapter wher we'll summarize immunizations and a quite extensive although not complete list of comorbidities.

IMMUNIZATIONS

• Children and adults with diabetes should receive routinely recommended vaccinations
• All people >=6 months should receive influenza vaccination, especially those with diabetes
• As for pneumococcal disease, PCV13 is recommended for children <2y, PPSV23 for individuals 2-64y, and additional PPSV23 for >65.
• Adults with diabetes 18-59y should receive 2-3 doses of hepatitis B vaccine and, if unvaccinated, consider 3 dosis for those >=60. 

ASSESSMENT OF COMORBIDITIES

 The ADA discusses here what they call diabetes comorbidities: conditions that are more frequent in diabetes than in age-matched non-diabetic individuals.

• AUTOIMMUNE DISEASES. People with type 1 diabetes should be at the beginning and periodically thereafter screened for autoimmune diseases, including thyroid disease, pernicious anemia and celiac disease. 
• CANCER. Diabetes increases risk for liver, pancreas, endometrium, colon/rectum, breast, and bladder cancer. Age- and sex-appropriate screenings as well as measures to reduce modifiable risk factors are encouraged.
• COGNITIVE IMPAIRMENT. Diabetes increases risk for dementia in 73%. In this case, treatment regime should be simplified and hypoglycemia risk avoided if possible. Both chronic hyperglycemia and recurrent hypoglycemia are related to cognitive impairment. In spite of early suggestions, neither nutrition nor statin use are clearly related to cognitive status. 
• NONALCOHOLIC FATTY LIVER DISEASE. Obesity and dyslipidemia are associated to NFLD. When suspected (elevated enzymes or suggestive ultrasound) specialized diagnostic assessment should be performed. Weight lose improve NFLD, as well as some medications (pioglitazone, vitamin E, liraglutide, gliflozins) but long term effects are unknown. 
• HEPATITIS C is more frequent in diabetes and worsens diabetic control. Its treatment, if effective, improves A1c in 0.45%.
• PANCREATITIS. Pancreatic exocrine dysfunction affect up to half of individuals with diabetes, and they have double risk of acute pancreatitis (AP). After an episode of AP, 1/3 of individuals develop diabetes. In chronic pancreatitis that need pancreatectomy islet autotransplantation should be considered. 1/3 of cases are insulin-free, and it can last up to 10 years. 
• FRACTURES. Risk is increased both in type 1 (RR 6.3) and type 2 (RR 1.7) diabetes. In type 1 DM low bone density plays an important role, but not in type 2 DM, where pathophysiology is less clear. In clinical trials, participants with DM had more fractures for any given T-score, FRAX score or age. Nevertheless, there are no specific recommendations to prevent them in diabetes. 
• SENSORY IMPAIRMENT. Deafness is more frequent in diabetes, twice as much in NHANES analysis, probably due to  neuropathy or vascular disease. Although not mentioned in the document, presence of diabetes and deafness in a family, particularly when maternally inherited, should raise suspiction for MIDD, a mitochondrial disease. Smell, but not taste, is also reduced in diabetes. 
• HIV infection on certain therapies (nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI)) may result in diabetes in >5% of cases, and prediabetes in >15%. NRTI affect fat distribution (atrophy and hypertrophy). Diabetes must be screened before initiating or switching antiretroviral therapy, and 3 months thereafter. In case it's detected, manteinance or withdrawal depend on clinical judgement. 
• LOW TESTOSTERONE IN MEN. Men with DM have lower testosterone than age-matched controls, but it's unclear whether this is due to obesity. The ADA recommends screening hypogonadism for men with reduced libido or erectile problems, but benefits of treatment are unclear. 
• OBSTRUCTIVE SLEEP APNEA. Obese individuals with diabetes have 4-10 higher risk of OSA. Patients with suggestive symptoms (snoring, sleepiness, witnessed apnea) should be screened. Treatment has clear benefits on QoL and blood pressure, less clear on glycemic control.
• PERIODONTAL DISEASE. It's not clear if it's more frequent in diabetes, but it's more severe. People with periodontal disease have more diabetes incidence, and it negatively affects diabetic control, but benefits of its treatment on diabetes are unclear. 

There's obviously a very important not mentioned comorbidity: COVID-19 infection. The ADA consensus was published in January and, unlike other, this section has not been so far re-evalated. Surely next year. There are extensive reviews about this topic in many recent publications, for example in The Lancet Diab & Endocrinol

Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes—2020

What I've written in this post, better expressed and much much more extensive you can find it in https://care.diabetesjournals.org/content/43/Supplement_1/S37

PATIENT-CENTERED COLLABORATIVE CARE

• The ADA recommends the physician should adapt his/her language to patients' characteristics, evaluate cultural barriers to communication, and have into account their preferences and beliefs. Common sense. 
• Diabetes care should be provided by a multidisciplinary team including primary care physicians, subspecialty physicians, nurse practitioners, physician assistants, nurses, dietitians, exercise specialists, pharmacists, dentists, podiatrists, and mental health professionals. ADA must be talking about the ideal world...

COMPREHENSIVE MEDICAL EVALUATION

 Initial visit must include 5 actions or aims:

• Confirm diagnosis of diabetes and classificate.
• Evaluate comorbidities and diabetic complications.
• If already known diabetes, record previous treatments and risk factor management.
• Involve the patient in a care management plan.
• Develop a care plan. 

These five actions are performed through the following checklist:

 

So you see there are 49 items for an initial visit and 43 for an annual visit, some of them may take quite a lot of time!! So, how many diabetic patients can you see in one morning if you want to do your job well?

TREATMENT PLAN. It must include: 

Every aspect of this plan will be extensively reviewed later in its corresponding chapter. 

Factors that increase hypoglycemia risk are:

• Insulin or secretagogue treatment
• Chronic kidney or hepatic disease
• Long-term diabetes
• frailty and older age
  
• Hypo unawarenesss or impaired contraregulatory response
• Cognitive impairment or physical disability
• Alcohol use
• Polypharmacy

 Referrals for initial care management include:

• Annual dilated eye exam
• Family planning for women of reproductive age
• Registered dietitian nutritionist for nutrition therapy
• Diabetes Self-Management Education and Support
• Dentist
• Mental health professional if indicated. 

Well, this post is getting too long, I'll leave the rest of the chapter for a second one that includes immunizations and assessment of comorbidities (autoimmune diseases, cancer, cognitive impairment, NEFA, hepatitis C, pancreatitis, fractures, HIV, male hypogonadism, obstructuve sleep apnea, periodontal disease).