Laura Cristoferi1,2, Stefano Ciardullo1,3, Pietro Invernizzi1,2, Gianluca Perseghin1,3, and Marco Carbone1,2 1 University of Milano‐Bicocca, Monza, Italy 2 European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy 3 Policlinico di Monza, Monza, Italy The liver plays a central role in the regulation of the metabolic homeostasis and is therefore a potential target of several metabolic and endocrine disorders. Often, endocrinologists find abnormal liver function tests (LFTs) in the context of common diseases such as thyroid disease and type 2 diabetes mellitus (T2DM), and these are frequent indications for referral to the liver specialist. Physicians should be aware of the potential impact of endocrine disorders on liver function and the development of chronic liver diseases, and of the effects of liver function on the endocrine system. For instance, obesity/visceral obesity, uncontrolled T2DM, hypothyroidism, growth hormone deficiency, and polycystic ovary syndrome might all lead to non‐alcoholic fatty liver disease (NAFLD). On the other hand, adrenal failure is increasingly reported in patients with end‐stage liver disease and in patients who have received a liver transplant, which suggests a bidirectional relationship between liver and endocrine functions. In this chapter, we review the most common causes of abnormal LFTs that endocrinologists face in their daily practice and provide advice on how to perform the first assessment, how to interpret those tests, and when to refer the patient to the liver specialist. The liver is the site of many metabolic pathways. It is the site of storage and release of carbohydrate, lipoproteins, vitamins, minerals, and metals, which are made available when required. In turn, the metabolic function of the liver is regulated by hormones secreted by the alpha (glucagon) and beta‐cells (insulin) within the endocrine component of the pancreas, the thyroid, and the adrenal glands. The liver maintains carbohydrates stores by synthesizing glycogen and generating glucose from lactate, pyruvate and amino acids (gluconeogenesis). In chronic liver diseases, it is common to observe altered fasting glucose, altered glucose tolerance, and insulin resistance, likely secondary to a decreased glucose uptake by muscle and reduced glycogen storage in the liver and muscle. In the lipid metabolism, the liver releases cholesterol and phospholipids, many of which are re‐esterified and packaged within lipoproteins. Bile acids are synthetized in the liver from cholesterol and they are both secreted into the bile, which represents the major route for cholesterol excretion. LFTs are commonly used in clinical practice to screen for liver diseases, to monitor the progression of a known chronic disease, and to monitor the effects of potentially hepatotoxic drugs. The last represents a common setting when abnormal LFTs are detected by endocrinologists. In addition, LFTs are routinely checked in patients with T2DM and obesity to stage multiorgan damage and explore the presence of NAFLD. Irrespective of the suspicion and of the level and duration of abnormality, all patients with abnormal LFTs should undergo liver etiology screen. It represents standard practice to retrieve previous blood test records before requesting additional investigations and referrals (Figure 8.1). The diagnosis of NAFLD and DILI largely relies on the exclusion of alternative causes of liver damage. These include a hepatitis B panel (HBsAg, HBsAb, HBcAb), hepatitis C antibody (with follow‐on polymerase chain reaction if positive), autoimmune panel, including anti‐mitochondrial antibody, anti‐nuclear antibody, anti‐smooth muscle antibody, serum immunoglobulins, serum ferritin (generally elevated in case of acute hepatitis as an acute‐phase protein), and transferrin saturation and ceruloplasmin. Anti‐liver kidney microsome antibody and anti‐transglutaminase antibodies should be requested, particularly in children and adolescents. An abdominal ultrasound is necessary to rule out bile duct and vessel obstruction, and chronic damage, with or without indirect signs of portal hypertension. The tests of liver function – bilirubin, albumin, international normalized ratio (INR) – and platelet count should be requested. Liver disease is generally silent and symptoms should not be awaited before LFTs are requested. Collecting a thorough medical history is relevant. The amount of alcohol drunk weekly should be estimated using units (or grams), bearing in mind the World Health Organization’s recommended maximum of ≤ 14 units/week in woman and ≤ 18 units/week in men. One unit of alcohol is equal to a small glass of wine (125 ml), half a can or 440 ml of lager/beer/cider 5.5% alcohol by volume (ABV), a small shot of spirits (25 ml, ABV 40%). However, when body mass index is greater than 35 kg/m2 and when chronic liver disease is already established, the risk of liver disease exponentially increases. The type of alcohol, drinking patterns, duration of exposure, and (generally unknown) individual/genetic susceptibility should be taken into account. Hepatic viral diseases are more common in injecting drug users, migrants, and people with multiple sexual partners; autoimmune liver disease is more common in patients with, or with a family history of, concomitant autoimmune diseases such as primary sclerosing cholangitis (PSC) in patients with inflammatory bowel disease, primary biliary cholangitis (PBC) in patients with autoimmune thyroid disease, Sjögren syndrome or scleroderma; iron storage can be suspected in patients with diabetes and/or brown skin. Table 8.1 Liver injury type and frequencies in most routinely used drugs in endocrinology.
8
Endocrinology and Metabolic Diseases (Including Diabetes)
Introduction
The Liver: Crossroads of Nutrient Homeostasis
When Will the Endocrinologist See Unexplained Abnormal Liver Function Tests?
Workup for Excluding Alternative Causes
Drug
Type
Frequency
Allopurinol
Hepatocellular, cholestatic or mixed
Minor liver test alterations in 2–6% of patients; rare acute liver injury
Dipeptidyl peptidase 4 inhibitors
Cholestatic or mixed liver injury that generally arises 1–4 weeks and resolves without residual injury within 1–3 months
Rare
Metformin
Cholestatic, hepatocellular, and mixed liver injury. Liver injury usually appears after 1–8 weeks, typically with symptoms of weakness and fatigue followed by jaundice; recovery is usually rapid after metformin is stopped
1% minor liver test alterations; acute hepatitis is rare
Repaglinide
Cholestatic, hepatocellular and mixed liver injury. Onset from 2–8 weeks; recovery after withdrawal
Rare
Second‐generation sulfonylurea
Cholestatic, hepatocellular and mixed liver injury. Onset within 3–12 weeks; rare instances of hepatic injury arising after many months or years of therapy have been reported, particularly soon after an increase in dosage
Rare
Troglitazone
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