FEATURE ARTICLE Elevated Liver Function Tests in Type 2 Diabetes Elizabeth H. Harris, MD iver function tests (LFTs) are postprandial states. Loss of insulin effect up-regulation of SREBP-1c and subse- commonly used in clinical prac- on the liver leads to glycogenolysis and quent simulation of de novo lipogenesis Ltice to screen for liver disease, an increase in hepatic glucose produc- in the liver leads to increased intracellu- monitor the progression of known dis- tion. Abnormalities of triglyceride stor- lar availability of triglycerides, promot- ease, and monitor the effects of poten- age and lipolysis in insulin-sensitive tis- ing fatty liver. This also increases VLDL tially hepatotoxic drugs. sues such as the liver are an early mani- assembly and secretion.1 Thus, hyperin- The most common LFTs include festation of conditions characterized by sulinemia might directly lead to hepatic the serum aminotransferases, alkaline insulin resistance and are detectable ear- insulin resistance with associated fatty phosphatase, bilirubin, albumin, and lier than fasting hyperglycemia. The pre- changes. prothrombin time. Aminotransferases, cise genetic, environmental, and meta- The excess in free fatty acids found such as alanine aminotransferase (ALT) bolic factors and sequence of events that in the insulin-resistant state is known and aspartate aminotransferase (AST), lead to the underlying insulin resistance, to be directly toxic to hepatocytes. measure the concentration of intracellu- however, is not fully understood.1 Putative mechanisms include cell lar hepatic enzymes that have leaked In animal models, chronic hyperin- membrane disruption at high concen- into the circulation and serve as a sulinemia is found to predispose the liver tration, mitochondrial dysfunction, tox- marker of hepatocyte injury. Alkaline to relative resistance to insulin. This is in formation, and activation and inhibi- phosphatase (AP), ␥-glutamyl transpep- characterized by a failure of insulin to tion of key steps in the regulation of tidase (GGT), and bilirubin act as signal an increase in insulin receptor metabolism.3 Other potential explana- markers of biliary function and substrate-2. Upregulation of sterol regu- tions for elevated transaminases in cholestasis. Albumin and prothrombin latory element-binding protein 1c insulin-resistant states include oxidant reflect liver synthetic function. (SREBP-1c) also occurs, leading to stress from reactive lipid peroxidation, The aminotransferases AST and ALT increased lipogenesis.2 Despite down- peroxisomal beta-oxidation, and are normally < 30–40 units/l. Elevations regulation of the insulin receptor sub- recruited inflammatory cells. The of aminotransferases greater than eight strate-2–mediated insulin signaling path- insulin-resistant state is also character- times the upper limit of normal reflect way in insulin-resistant states, the ized by an increase in proinflammatory either acute viral hepatitis, ischemic hep- cytokines such as tumor necrosis fac- atitis, or drug- or toxin-induced liver IN BRIEF tor-␣ (TNF-␣), which may also con- tribute to hepatocellular injury. In pre- injury. Much more common than Individuals with type 2 diabetes have liminary studies, an increased patients with acute hepatitis, however, a higher incidence of liver function frequency of specific TNF-␣–promoter are patients with chronic mild elevation test abnormalities than individuals polymorphism was found in nonalco- of aminotransferases, or AST and ALT who do not have diabetes. Mild holic steatohepatitis (NASH) patients, < 250 units/l for > 6 months. chronic elevations of transaminases suggesting a possible genetic link or Chronic mild elevation of transami- often reflect underlying insulin resist- predisposition to fatty liver found in nases are frequently found in type 2 dia- ance. Elevation of transaminases insulin-resistant states.4 betic patients. This article will provide a within three times the upper limits of The above theories all attribute ele- review of the pathology, incidence, caus- normal is not a contraindication for vated transaminitis to direct hepatocyte es, and drug therapy related to type 2 starting oral antidiabetic or lipid- injury. It is also hypothesized that eleva- diabetic patients with elevated LFTs. modifying therapy. In contrast, antidi- tion in ALT, a gluconeogenic enzyme abetic agents have generally been whose gene transcription is suppressed Theories Behind LFT Elevation shown to decrease alanine amino- by insulin, could indicate an impairment in Diabetes transferase levels as tighter blood glu- in insulin signaling rather than purely The liver helps maintain normal blood cose levels are achieved. glucose concentration in the fasting and hepatocyte injury.5 CLINICAL DIABETES • Volume 23, Number 3, 2005 115 FEATURE ARTICLE Can Elevated LFTs Predict the betes. The authors concluded that higher abnormal LFTs who were awaiting liver Development of Diabetes? ALT is a risk factor for type 2 diabetes biopsy. Sixty-eight of the patients had GGT is a nonspecific marker that is and indicates a potential role of type 2 diabetes; four had type 1 diabetes. known to rise in patients with type 2 increased hepatic gluconeogenesis All of the patients had hepatomegaly or diabetes. In epidemiological studies, it and/or inflammation in the pathogenesis abnormal LFTs. They had normal blood has a positive association with alcohol of type 2 diabetes. counts, serum electrolytes, and renal intake, cigarette smoking, coronary heart function. None had decompensated heart disease, BMI, systolic blood pressure, Incidence of Elevated LFTs in failure. Only 5 gave a history of social serum triglyceride, heart rate, uric acid, Diabetes drinking; the other 67 patients were clas- and hematocrit. It has an inverse associ- Salmela et al.10 studied the prevalence of sified as abstainers. ation with physical activity level.6 abnormal LFTs and their relationship to Of the 72 patients who underwent Because GGT increases in diabetes, and clinical findings in 175 unselected dia- liver biopsy, all 4 with type 1 diabetes increases as BMI increases, it has been betic outpatients in Finland. One hun- had normal liver histology, but only 5 of proposed as another marker of insulin dred and eighteen patients were classi- the 68 with type 2 diabetes had normal resistance. fied as having type 2 diabetes and 57 as liver histology. The most commonly ele- To determine whether elevated GGT having type 1 diabetes. Of those with vated LFT in the nine patients with nor- could predict the development of type 2 type 2 diabetes, 33 patients used insulin mal histology included bilirubin and AP. diabetes, a prospective cohort study of in addition to diet and oral hypo- ALT was less frequently elevated, and 7,458 nondiabetic men aged 40–59 years glycemic drugs including sulfonylurea GGT was not elevated at all. was conducted for 12 years.7 Mean and metformin. None of the patients had Of the 63 patients with abnormal liv- serum GGT at the start of the study was known chronic liver disease, and none er histology, 48 had fatty liver or steato- significantly higher in the 194 men who had clinically significant diabetic sis with nonspecific inflammatory developed type 2 diabetes than in the rest nephropathy. Hemoglobin A1c (A1C) changes, whereas 14 had evidence of of the cohort who did not develop dia- averaged 11.2 ± 2.4%. fibrosis. GGT and ALT were most com- betes (20.9 vs. 15.3 units/l, P < 0.0001). LFTs measured included albumin, monly elevated. As histology worsened The association was independent of total bilirubin, AST, ALT, AP, GGT, and (steatosis to inflammation to fibrosis), serum glucose and BMI. However, when serum concentrations of cholic acid and there was no significant difference in GGT was added to a model for predict- chenodeoxycholic acid. Fifty-seven per- mean values of ALT and GGT. There- ing the development of type 2 diabetes, it cent of the 175 diabetic outpatients (100 fore, although abnormal LFT results are did not improve the power of BMI and subjects) had at least one abnormal LFT; common in diabetes, especially in over- glucose for predicting the development 27% (48 subjects) had at least two abnor- weight type 2 diabetic patients, they are of type 2 diabetes. mal tests. The type 2 diabetic patients not reliable in predicting histological Ohlson et al.8 found elevated ALT in more frequently had elevated ALT (22.9 changes in the liver. nondiabetic Swedish men to be a risk vs. 5.3%) and GGT (23.7 vs. 10.5%) lev- In a larger study, Erbey et al.11 ana- factor for type 2 diabetes, independent of els than those with type 1 diabetes. On lyzed 18,825 noninstitutionalized obesity, body fat distribution, plasma the other hand, patients with type 1 dia- patients within the United States with an glucose, lipid, AST, bilirubin concentra- betes more frequently had elevated oversampling of African Americans and tions, and family history of diabetes. bilirubin levels (21.1 vs. 10.2%). Howev- Mexican Americans. Of the total sample, With similar results, Vozaroza et al.9 fol- er, increases in LFTs were rarely more 4.1% had elevated ALT, and 6.7% had lowed 451 nondiabetic Pima Indians for than twice the upper limit of normal. type 2 diabetes. Of those with type 2 dia- an average of 6.9 years to determine Multivariate analysis showed BMI betes, the prevalence of elevated ALT whether hepatic enzyme elevations could > 25 kg/m2 and poor diabetic control was 7.8%, compared to a 3.8% preva- be linked to the development of type 2 (fasting blood glucose > 216 mg/dl) lence in those without diabetes. The diabetes. At baseline, ALT, AST, and were the most significant clinical vari- prevalence of ALT elevation greater than GGT were related to percent body fat. ables associated with elevated ALT and three times normal was not significantly After adjustment for age, sex, body fat, GGT. Elevated ALT was also associated different between the nondiabetic and whole body insulin sensitivity, and acute with onset of diabetes within the past 4 diabetic patients (0.4 vs.