Comorbid Diabetes and Hepatic Cirrhosis

Comorbid Diabetes and Hepatic Cirrhosis 

• Liver disease encompasses a broad spectrum of conditions from mild disease with minimal implications to full-blown and decompensated disease with profound metabolic and circulatory changes.
• •Metabolic syndrome refers to a group of conditions that are strongly associated with risks for cardiovascular disease, diabetes mellitus (DM), and liver disease, among others. Characteristics include the following:
  • 1.Large waist circumference
  • 2.Elevated triglyceride level
  • 3.Low low-density lipoprotein (LDL) cholesterol
  • 4.High blood pressure
  • 5.Insulin resistance
• •Nonalcoholic fatty liver disease (NAFLD): Condition in which fat accumulates in liver cells causing a “fatty liver,” no significant alcohol use, and mimicking features of classic alcoholic liver disease.
• •Nonalcoholic steatohepatitis (NASH): Refers to a fraction of all people with NAFLD in whom fat accumulation is associated with inflammation, fibrosis, and potentially full-blown cirrhosis.
  • 1.NAFLD/NASH. There is now a still somewhat controversial proposal to replace the term NAFLD with metabolic-associated fatty liver disease (MAFLD). 
  • 2.Fat is now recognized as a reservoir of agents (cytokines, etc.) that cause damage to multiple organs including blood vessels and liver.
• •Liver disease in the patient with DM can be divided into three patient categories:
  • 1.Direct consequence and component of DM-associated metabolic syndrome
  • 2.DM/metabolic syndrome as confounder that worsens the outcome of concomitant liver disease
  • 3.Liver disease, usually advanced, requiring modifications that deserve specific attention in the patient with DM (medications, preparation for procedures, etc.).
• •In addition, patients may occasionally present with confusing presentations of hypoglycemia.

Liver Disease, Metabolic Syndrome, Insulin Resistance/DM

• •The epidemic increase of obesity worldwide is directly linked to a dramatic increase in patients with metabolic syndrome, accompanying insulin resistance and the entities of nonalcoholic steatohepatitis/nonalcoholic fatty liver disease (NASH/NAFLD), potentially renamed MAFLD. It took years before the histopathologic features of “alcoholic liver disease in nonalcoholic patients” (patients falsely accused of alcohol abuse), and already described in the context of DM type 2 as early 1970, were put into the context of metabolic syndrome. In addition, there is the somewhat more recent recognition that insulin resistance is not only frequent in patients with obesity, but may also occur in lean people. It is now estimated that as many as 1 in 4 worldwide may have fatty liver, a somewhat unknown fraction having variable degrees of damage (fibrosis, cirrhosis), and with geographic and ethnic differences. Asian patients with otherwise similar characteristics as other patients may sustain less damage from fat accumulation. 
• •NAFLD/NASH tends to be a progressive disease. The prevalence of the problem implies that even if only a small percentage of patients develop advanced liver disease (cirrhosis), the initial fear has already become reality: NASH/NAFLD has become a leading cause of cirrhosis, hepatocellular carcinoma, and a leading indication for liver transplantation. 
• •NASH-related cirrhosis may go unrecognized, specifically also if, in more advanced stages of the disease, fat disappears from these livers; cryptogenic cirrhosis may be NASH related, but likely less frequently than originally was postulated. 
• •After breakthroughs in management of hepatitis B and C, the major focus of attention in clinical management and research of the hepatology community has shifted toward the major public health crisis of morbid obesity and NAFLD. The complex and diverse nature of contributors to obesity and NASH are increasingly appreciated and include changes in microbiome, possibly in part related to use/abuse of antibiotics early in life, and at the same time a potential role to influence this with probiotics or antibiotics, and there is a role for genetic determinants. It has led to a less judgmental approach to patients.
• •Like any patient with underlying liver disease, patients with NAFLD are at increased risk of fatal outcome if infected with hepatitis A virus (HAV) or hepatitis B virus (HBV) and need vaccination if not immune.
• •A multidisciplinary input is mandatory to tackle the problem, and opportunities for expansion and improvement are major. Joint calls to action of liver and endocrinology societies are in progress.

Other Patients with Liver Disease and DM

• •Patients with any liver disease who also have DM or insulin resistance deserve specific considerations:
  • 1.Treatment may enhance DM: Steroids for autoimmune hepatitis or other diseases are a classic example, and they may cause iatrogenic DM, but also overweight and NASH.
  • 2.Treatment may modify DM/insulin resistance and illustrates the systemic effects of certain diseases. Eradication of hepatitis C virus (HCV) infection, now easily accomplished with oral medications, is an example. The outcomes in large patient cohorts support the concept that HCV is more than liver disease only. Systemic effects including cardiovascular and other organ damage, negatively influencing live expectancy. However, the impact of eradication on insulin resistance is varied. 
  • 3.The patient with advanced liver disease and DM may have other comorbidities (cardiac failure, renal failure, etc.) that need to be incorporated in management plans, for example, for the treatment of portal hypertension. The recognition of profound hemodynamic changes as a consequence of progressing liver disease are too often underappreciated: peripheral vasodilation, central vasoconstriction, and hyperdynamic circulation. Hypertension may “disappear” when liver disease progresses. If beta-blockers are needed, where possible, selective beta-blockers should be switched to nonselective beta-blockers to prevent bleeding of esophageal varices and decompensated liver disease. The potential of enhancing DM by beta-blockers is usually a minor and surmountable risk when compared with the benefits.
  • 4.Treatment to prevent acute or chronic rejection after liver transplantation may lead to DM. This applies not only to steroids, but also to other immunosuppressants that may enhance cardiovascular disease, hyperlipidemia, and hypertriglyceridemia.
  • 5.Patients with severe acute or advanced chronic liver disease and DM are more prone to develop hypoglycemia in the context of diminished or absent glycogen storage.
    • a.Oral agents such as sulfonylureas may become increasingly risky and may require a switch to an insulin-containing regimen.
    • b.Fasting for medical, dental, or surgical procedures requires alertness and awareness about the risks of prolonged fasting and profound hypoglycemic attacks if not appropriately dealt with.
    • c.Impending renal failure puts the patient at risk for contrast-related renal failure. Minor increases in creatinine may be missed in the screening of patients preceding contrast-enhanced procedures.
  • 6.Patients with acute liver failure (typically high bilirubin, prolonged international normalized ratio [INR]) may also develop hypoglycemia and change in mental status, and this needs recognition in the differential diagnosis of portosystemic encephalopathy.
  • 7.Patients with advanced liver disease are prone to develop hepatocellular carcinoma that may cause hypoglycemia through two different pathways, which need to be differentiated from excess dosages of insulin:
    • a.Very advanced liver disease with rapid diffuse tumor growth and weight loss may lead to insufficient glycogenreserve (type A hypoglycemia) with suppressed insulin and c-peptide levels, increased glucagon.
    • b.Neuroendocrine differentiation of hepatocellular carcinoma (HCC) may in a subgroup of these patients be functional and cause paraneoplastic phenomena such as erythrocytosis, hypercalcemia, or hypoglycemia associated with the defective production of pro-IGF2 by hepatocytes leading to increased glucose uptake in cells and hypoglycemia (type B hypoglycemia).

 Treatment

Approach to Treatment

• •The challenge is to integrate optimal treatment of liver disease with optimal treatment of DM and frequently occurring other comorbidities (specifically cardiovascular and renal disease).
• •Multidisciplinary input is essential (specialists, primary care provider, dietitian, etc.).
• •Recognition in which of the categories your patient belongs (see above).
• •Liver disease management may focus on broad or specific goals:
  • 1.Treatment of viral hepatitis, autoimmune hepatitis, Wilson’s disease, and others
  • 2.Preventing or managing complications of advanced disease (ascites, variceal hemorrhage, encephalopathy, sarcopenia)
  • 3.Disease management after liver transplantation (with or without kidney), specifically with an eye on complications of immunosuppressive therapy including cardiovascular and renal disease (common in patients with DM)
• •A considerable number of patients may have or develop NASH. Although staging of potential disease is important, the hallmarks of treatment (decrease body weight, increase exercise, lifestyle modifications) will for now remain identical. In the near future specific NASH treatment agents (many in the pipeline) may be added to the armamentarium. Advanced NASH is associated with HCC risk (see below):
  • 1.Detailed NASH diagnostics may increase the burden to the patient, who often already has multifactorial contributors to NASH (obesity, joint problems, exercise limitation, depression, poverty), and the potential predictive value of histopathologic features for long-term prognosis may have very limited value relative to costs (both financial and emotional) and implications for management.
• •A diagnostic protocol needs to be in place for diagnosing NASH. Liver biopsy is still deemed the gold standard, but realistically not recommended other than in specific cases (cost, cost-effectiveness, acceptability). Liver stiffness can be assessed with elastography (Fibroscan R), which may identify high-risk groups for complications. A variety of sometimes costly alternatives are proposed including magnetic resonance elastography. As outlined above, it is essential to decide if recommendations would change dramatically if more fibrosis was identified and what level of accuracy is required outside research settings.
• •Patients with liver disease and DM may, depending on disease evolution, need treatment(s) that affect management of other comorbidities and/or interfere with DM management. This specifically includes dietary needs, medications that interfere with cardiovascular manifestation of liver disease (see below), and ascites.
  • 1.High-caloric/high-protein diet, divided over 4 to 6 meals/snacks daily, is indicated in patients with advanced/decompensated liver disease.
  • 2.Sodium restriction (advanced liver disease is associated with retention of water and sodium, but water in excess) while keeping food palatable. It is essential to communicate this with a dietitian, and, in case of advanced liver disease, a physical therapist: Muscular training is important to prevent sarcopenia and to enhance the metabolism of ammonia.
  • 3.Diuretics (in particular spironolactone and furosemide) to control ascites may also lower blood pressure and may require adjustment of other agents.
  • 4.Beware of osmotic diuresis in poorly controlled diabetes that may enhance renal failure and portosystemic encephalopathy.
  • 5.Nonselective beta-blocker therapy or replacement of selective beta-blockers by nonselective beta-blocker therapy is important for the prevention of variceal bleeding or rebleeding (primary and secondary prophylaxis) and prevention of decompensation of liver disease. The goal is to reduce splanchnic arterial flow, and therefore reduce portal venous flow with lower variceal inflow/pressure, reduce bleeding and rebleeding risk, and—increasingly recognized—improve life-expectancy by lowering the risk of decompensation. If not properly communicated and understood, excessive lowering of pressures may have detrimental consequences (see therapy guidance). In addition, patients with advanced liver disease may be exquisitely sensitive to the effect of nonselective beta-blocker therapy and be prone to renal failure when given NSAIDs that may lead to worsening of ascites (see also prevention of primary and secondary variceal hemorrhage and disease outcome, role of beta-blockers).
  • 6.Liver disease induced by statins is very rare, whereas mild and sometimes transient elevations of liver tests are common. Frequent monitoring is associated with a very questionable cost-benefit ratio. Minor elevations of transaminases (<5 times upper limit of normal) may lead to unnecessarily withholding and depriving patients from beneficial agents. It is becoming increasingly clear that “statins are good for the liver,” including lowering of portal pressure. The relatively rare occurrence of significant rhabdomyolysis may be associated with more significant test abnormalities and symptoms.
• •Acute and progressive chronic liver disease is associated with decreased glycogen reserve making the patient prone to hypoglycemia, due to the inability to rapidly mobilize glucose. This may make patients more prone to drug-induced hypoglycemia. Hypoglycemia should be appreciated as the potential expression of more severe liver failure.
• •Preventive aspects include the following:
  • 1.Monitor for the development of hepatocellular carcinoma: 6-monthly cross-sectional imaging (ultrasound, computed tomography, or magnetic resonance imaging with or without alfa-fetoprotein levels) in at-risk groups (advanced disease = advanced fibrosis).
  • 2.Patients with underlying multiple-etiologic liver disease (viral hepatitis, alcohol, others) and patients with family history of HCC are at increased risk, and NASH can act as a major negative confounder of disease outcome.
  • 3.Vaccination for HAV and HBV: All patients with a compromised liver are at increased risk for fatal outcome of viral hepatitis.
  • 4.Discourage alcohol consumption, the damaging effects of which are greater in women than in men.

Nonpharmacologic & Supportive Care

• •Diet:
  • 1.The combination of liver disease and DM should lead to a diet that provides adequate calories based on body weight and scheduled around medications (oral hypoglycemics, insulin).
  • 2.Presence of NAFLD/NASH (drivers of disease outcome): Caloric restriction, focus on weight loss if overweight. Dietary modifications uncertain: Mediterranean diet suggested by some. Target weight loss 7% to 10% of total body weight, 500 to 1000 calorie deficit daily.
  • 3.Presence of advanced liver disease (patient with muscle wasting/sarcopenia, ascites, jaundice, portosystemic encephalopathy [PSE]), patients at risk of breaking down their own bodies. It is no longer the time to focus on significant weight loss, which encompasses risk per se.
    • a.High calorie
    • b.High protein
    • c.Divided in multiple portions/snacks each day
• •Lifestyle focus should be part of a program.
  • 1.Fitness in general with muscle strengthening exercises that not only focus on improved DM control and general condition, but also enhance muscular metabolism of ammonia, important in PSE patients.

Pharmacologic Therapy

First-Line Treatment

Many specific NASH drugs are in the pipeline, but none is formally approved for the indication.

Treatment Procedures

• •Weight loss should first be attempted with dietary measures (team support, etc.) but in case of morbid obesity gastric-bypass procedures (surgical or endoscopic) should be considered with a low threshold in patients who have tried for too long. It is also feasible in certain categories with advanced disease. In experienced hands this tends to reduce multiple comorbidities (including improved DM type 2 control).
• •Beware: Aggressive/drastic weight loss remains risky and can lead to worsening of liver disease.

Follow-Up

• •Liver disease may be suggested by abnormal liver tests, abnormal imaging results (nodular liver), or signs of even more advanced disease such as variceal hemorrhage or bleeding varices.
• •Patient should undergo diagnostic evaluation like any patient with (persistent) abnormal liver test or suspected liver disease otherwise.
• •Physical examination may reveal indicators that suggest advanced disease (jaundice, muscle wasting, flapping tremor, gynecomastia, “spider angiomas,” edema, low blood pressure, etc.). Examination may be remarkably negative.
  • 1.Etiology with at least testing for viral hepatitis, apha-1 antitrypsin deficiency, iron markers (SeFe, iron binding capacity), and others depending on further disease characteristics (see evaluation of abnormal liver tests or abnormal liver imaging).
  • 2.Severity:
    • a.Laboratory tests:
      • (1)Bilirubin, transaminases, alkaline phosphatase, gamma-GT
      • (2)Complete blood count including platelet count
      • (3)Prothrombin time/INR
      • (4)Albumin
      • (5)Glucose
    • b.Imaging:
      • (1)Cirrhotic appearance with/without space-occupying lesion
      • (2)Splenomegaly, collateral circulation
      • (3)Ascites
  • 3.Treatable aspects:
    • a.Viral hepatitis B and C (HBV DNA? HCV RNA and genotype?)
    • b.Autoimmune hepatitis (context, autoimmune markers)
    • c.Modification of immunosuppression (lowering in case of cytomegalovirus hepatitis in transplant patients, etc.)
  • 4.Develop management plan based on findings. The patient with more advanced disease will usually be seeing a hepatologist. The patient with DM who happens to have the suggestion of beginning or somewhat advanced disease will benefit from the physician who treats DM to know what preventive and proactive management should benefit the patient.

Monitoring

Preventive Aspects

• •Stage disease severity (noninvasive mostly)
  • 1.Elastography
  • 2.Liver biopsy in rare cases: What would be a result that changes management?
  • 3.If no signs of advanced disease: Follow-up per 2 to 3 yr?
• •If advanced fibrosis/cirrhosis
  • 1.Is screening for varices indicated? No if platelets >150, stiffness <20 KPa (Baveno criteria)
  • 2.If varices: Institute nonselective beta-blocker therapy
• •HCC monitoring
• •Vaccinate according to recommendations and specifically for HAV and HBV as indicated