The following is a discussion of
diabetes management in patients with liver disease. There are points
everyone should be aware of and include in their management.
Lifestyle modification
Treatment of type 2
diabetes in patients with liver disease may be compromised by poor
nutritional status and general health. More than 50% of patients
with severe liver disease are malnourished. A number of uncontrolled
studies indicate that weight loss decreases hepatic steatosis. The
durability of weight loss on hepatic steatosis remains to be
determined. Low-glycemic, low-calorie diets with a weight loss of
1–2 kg/week seem reasonable. Low-fat diets should be avoided.
Exercise improves peripheral insulin sensitivity, albeit not specific
to patients with diabetic liver disease. Alcohol should be avoided
not only because of its toxic effects on the liver, but also because
of its high caloric content and potential interaction with
sulfonylureas.
Pharmacologic therapy
Drug therapy of type 2 diabetes in
patients with liver diseases is, for the most part, the same as for
those without liver disease. While there are theoretical concerns
about altered drug metabolism and hepatotoxicity, only patients with
evidence of liver failure such as ascites, coagulopathy, or
encephalopathy have altered drug metabolism. Furthermore, there is
no evidence that patients with liver disease are predisposed to
hepatotoxicity. Underlying liver disease, however, may compromise
the diagnosis and increase the severity of drug-induced liver
disease.
First-line therapy
with metformin is appropriate in most patients but not recommended in
patients with advanced hepatic disease because of a perceived
increased risk of lactic acidosis. Given that insulin resistance is
the core defect in fatty liver disease, the case can be made for
thiazolidinediones (TZDs) as front line therapy in these patients.
Recent trials with pioglitazone and rosiglitazone have shown
improvement in ALT and liver histology. Weight gain is a concern
with TZDs, and cost is prohibitive for many patients. If metformin
or TZDs are contraindicated, drug therapy can begin with a
secretagogue such as a sulfonylurea with rapid advancement to insulin
if glycemic control is not achieved.
Insulin promoters.
Sulfonylureas are
generally safe in patients with liver disease but may not overcome
the insulin resistance and defects in insulin secretion seen in
patients with coexistent alcoholic liver disease and pancreatic
damage. Sulfonylureas with a short half-life such as glipizide or
glyburide are preferred in these patients. Patients with
decompensated cirrhosis, i.e., encephalopathy, ascites, or
coagulopathy, may have a reduced ability to counteract hypoglycemia,
and thus, the response to therapy should be monitored closely.
Historically, chlorpropamide was associated with hepatitis and
jaundice.
Biguanides.
Metformin may be
particularly useful in obese patients in whom it may cause mild
weight loss. It is relatively contraindicated in patients with
advanced liver disease or in binge drinkers because it may predispose
to lactic acidosis. It is unclear whether the liver disease or
alcohol is the predisposing factor. Metformin has not been reported
to cause hepatotoxicity and has shown some benefit in patients with
NAFLD.
α-Glucosidase inhibitors.
The α-glucosidase
inhibitors may be particularly useful in patients with liver disease
because they act directly on the gastrointestinal tract to decrease
carbohydrate digestion and thus glucose absorption, thereby
decreasing postprandial hyperglycemia
Acarbose frequently
causes mild transient elevations of ALT and, on rare occasions,
severe liver disease. While the labeling of acarbose has a warning
for patients with liver disease, it appears to be safe and effective
in patients with hepatic encephalopathy and type 2 diabetes.
Miglitol, another α-glucosidase inhibitor, has not been associated
with hepatotoxicity.
TZDs.
TZDs may be
especially useful because they enhance insulin sensitivity, the
underlying defect in NAFLD. In pre-approval clinical trials of
rosiglitazone and pioglitazone, threefold elevations of ALT were seen
with the same frequency for rosiglitazone (0.26%), pioglitazone
(0.2%), and placebo (0.2 and 0.25%)
It is currently
recommended that serum ALT levels be evaluated before the initiation
of rosiglitzone and pioglitazone therapy and that therapy not be
initiated if there is evidence of active liver disease or if the
serum ALT level exceeds 2.5 times ULN (product labeling, 2005).
Monitoring is recommended periodically thereafter as clinically
indicated rather than every 2 months as previously recommended.
Paradoxically, TZDs are emerging as the treatment of choice for NASH
(nonalcoholic steatohepatitis).
Insulin.
Insulin treatment is frequently required in patients with diabetes
and liver disease. Insulin requirements, however, may vary. For
example, in patients with decompensated liver disease, the
requirement may be decreased due to reduced capacity for
gluconeogenesis and reduced hepatic breakdown of insulin. However,
patients with impaired hepatic function may have an increased need
for insulin due to insulin resistance. Thus, careful glucose
monitoring and frequent dose adjustments of insulin may be necessary.
In patients with hepatic encephalopathy who require
high-carbohydrate diets, resulting in postprandial hyperglycemia,
rapid-acting insulin analogs such as insulin lispro, aspart, or
glulisine may be particularly useful.
Other drugs used in the management
of disorders associated with type 2 diabetes
Statins are
frequently used in patients with type 2 diabetes to treat
hyperlipidemia and prevent cardiovascular events. Statin therapy,
like all cholesterol-lowering therapy including bariatric surgery,
causes minor but transient elevations in liver enzymes. However, the
liver adapts with continuing therapy, and there are no long-term
consequences of these abnormalities. Severe liver damage and liver
failure are very rare. Paradoxically, statins are currently used to
treat NAFLD, and recent studies suggest that statins are
hepatoprotective in patients with HCV (hepatitis C virus).
All of the ACE
inhibitors have been implicated in hepatic injury including fulminant
hepatic failure. The reactions are mostly hepatocellular, but
cholestatic reactions have also been reported. Although losartan has
been associated with hepatotoxicity, it has also been used to treat
fatty liver disease. There are no current recommendations for
hepatic monitoring of these idiosyncratic events.
Even aspirin is
potentially hepatotoxic although at very high doses. Hepatotoxicity
has not been described at doses used for cardioprotection.
