Dm & liver

1

Diabetes & liver(Updates)

Alaa Wafa , MD.Associate Professor of Internal Medicine

PGDIP DM Cardiff University UKDiabetes & Endocrine Unit.

Mansoura University

Agenda Agenda

Magnitude of the problem

Spectrum of liver disease in type 2 diabetesSpectrum of liver disease in type 2 diabetes

Management of diabetes in patients with Management of diabetes in patients with concomitant liver disease.concomitant liver disease.

Management of liver disease in patients with Management of liver disease in patients with type 2 diabetes.type 2 diabetes.

Magnitude of the problem

Adapted from http://www.indexmundi.com/egypt/demographics_profile.html , https://www.cia.gov/library/publications/the-world-factbook/geos/eg.html , http://en.worldstat.info/World accessed 22-2-2014

http://www.indexmundi.com/egypt/demographics_profile.html

https://www.cia.gov/library/publications/the-world-factbook/geos/eg.html

http://en.worldstat.info/World

Almost half of all people with diabetes live in just three countries

ChinaIndiaUSA

IDF2013

Diabetes & Liver disease

Both problems have an important

interaction considering etiology & the

presence of any problem of each affect

the management of the other.

Spectrum of liver disease in Spectrum of liver disease in type 2 diabetestype 2 diabetes

Spectrum of liver disease in type 2 Spectrum of liver disease in type 2 diabetesdiabetes

1. Abnormal liver enzymes

1.Elevation of (ALT),, is common in patients with type 2

diabetes ( 24%)( 24%).

2.Evaluation of asymptomatic individuals with mild

elevations of ALT and AST reveals that 98% have liver

disease most commonly, fatty liver disease and

chronic hepatitis

Belcher G, Schernthaner G: Changes in liver tests during 1-year treatment of patients with type 2 diabetes with pioglitazone, metformin or gliclazide. Diabet Med 22:973–979, 2005


2. Non alcoholic fatty liver disease (NAFLD)• It is defined as fatty liver disease in the absence of 20 g

alcohol/day. • NAFLD consists of a spectrum of liver disease from

steatosis (fatty infiltration of the liver) to nonalcoholic

steatohepatitis (NASH), which consists of steatosis plus

inflammation, necrosis, and fibrosis.• The prevalence of NAFLD in diabetes is estimated at 34–34–

74%74% and, in diabetes with obesity, at virtually 100%100%.Pinto HC, et al: Nonalcoholic steatohepatitis: clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci 41:172–179, 1996

High prevalence of NAFLD* in Patients with T2DM and Normal Plasma AST/ALT Levels

0

20

40

60

80

100

Non-obese Obese

Pre

vale

nce

(%)

n=103

*Screened by the gold standard magnetic resonance and spectroscopy(Portillo et al, submitted)

Prevalence of NAFLD in predominantly obese patient with or without T2DM according to different diagnostic tools

Cardiovascular disease OSA

Vitamin D deficiency

Vitamin D deficiency

PCOS

HyperuricemiaAdenomatous polyps

Elevated ferritin

Hypothyroidism

Pancreatic steatosis

Metabolic Consequences of NAFLD

MR Elastography (MRE) in NAFLD


3. Non alcoholic Steatohepatitis (NASH)• While once considered a benign process, NASH has

been found to lead to cirrhosis and, in some cases, to hepatocellular carcinoma.

• Of patients with NAFLD, 50% have NASH50% have NASH and 19% have 19% have cirrhosis cirrhosis at the time of diagnosis.

• Pathogenesis of steatosis :Insulin resistance resulting in lipolysis, which increases circulating free fatty acids, which are then taken up by the liver as an energy source.

• The fatty acids overload the hepatic mitochondrial oxidation system, leading to accumulation of fatty acids in the liver.

Marchesini G, et al: Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:917–923, 2003

Red Flags for NASH• Age

• Gender

• Hispanic

• HTN

• Obesity

• Diabetes

• ALT and AST level• AST/ALT ratio

• Insulin level

• PNPLA3

Non lab test or imaging study will be able predict with 100% accurancy

For me, the more risk factors .. The more concerned I become

Natural history of NASH

NASH

Cirrhosis

Liver death

Fibrosis

Liver transplant

HCC

15-20%40-50%

2-3%/yr

30-40%

2-12% of US population Risk of death in NASH1st CVD2nd Cancer3rd Liver

• Currently, liver biopsy is the only way to diagnose NASH

• Liver biopsy is classify such as large population

• Impractical• Expensive• Invasive• Variability

• Need for clinical predication rules and novel biomarker of NASH

Types of biomarkers

• Moacular– Genomic– Proteomic

• CK-18• ELF• HA RBP-4• IU panel• Younossi panel

– Lipiomic• Oxidized FA• Non HDL cholesterol• Small dense LDL

– Metabolomic– Hydrid panels

• NAFIC panel

• Imaging– MR - based

• MRI-PDFF• MRS• MRE• Diffusion-weighted

imaging – ultrasound

• USG• Transient USG• ARFI

– CT

Spectrum of liver disease in type 2 diabetes

4. Hepatitis C in diabetes

Recent study shows that insulin resistance is a risk factor for esophageal varices risk factor for esophageal varices in hepatitis C virus cirrhosis.

Recent studies suggest that the core protein of HCV impairs insulin receptor substrate signaling, which plays an important role in the metabolic effects of insulin.

Cammà C, et al. Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis. Hepatology. 2009;49(1):195-203

Insulin Resistance and Hepatitis

• HCV infection contributes development of IR and

• Increase risk of development of T2DM

• Insulin resistance prevalence in CHC:

• 32% - 70%

• Insulin resistance associated with:

• Viral load

• fibrosis

Association of insulin resistance and fibrosis progression

• IR associated with moderate to serve inflammation.

• HOMA increased significantly with fibrosis stage (p=0.001) by logistic regression, IR independently associated with significant fibrosis 0

3

6

9

12

15

Fibrosis (METAVIR)F0-F1 F2 F3 F4

HO

MA

-IR

Moucari et al, Gastroenterology 2008; 134:416-423

Good News • HCV eradication rates are now 90% or greater even for

cirrhosis

• Sustained virologic response associated with decreased rates of progression to decompensation.

• Future is very bright. Newer direct acting antiviral expected this year will be:

- All oral

-Minimal side effects

-Cure rate more than 90%

ADA Scientific Sessions San francisco 2014

5. Cirrhosis in diabetes

The association of cirrhosis and diabetes is

complicated by the fact that cirrhosis itself is

associated with insulin resistance.

Wanless IR, Lentz JS: Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12:1106–1110, 1990

Etiology of liver cirrhosis most frequently Etiology of liver cirrhosis most frequently associated with diabetes mellitusassociated with diabetes mellitus


6. Hepatocellular carcinoma in diabetes• Numerous studies have confirmed a four fold four fold

increased prevalenceincreased prevalence of hepatocellular carcinoma in patients with diabetes as well as an increased prevalence of diabetes in patients with HCC.

• Patients with HCC and DM have a mortality risk mortality risk higherhigher than patients with HCC without DM.

• In another study involving 160 patients suffering from HCC, those who had DM had a 1-year mortality rate higher than those patients without DM. Additionally, they had more extensive disease.

El-Serag HB, et al: Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126:460–468, 2004

Hepatocellular carcinoma association with diabetes

Hepatocellular carcinoma

Diabetes2-4 fold

1) Increased risk persists after stratifying for age, gender, ethnicity, viral hepatitis, alcohol, iron overload

2) Synergistic with alcohol and viral hepatitis.

J Natl cancer Inst 1997; Lawson DH, QJ Med 1986; La Vecchia C, Intl J cancer 1997; HO, J Natl cancer Inst 1996; Yuan J M, Cancer 2004; Davila J A, Gut 2005; Hasson M M ,Hepatology 2002

Management of diabetes in patientswith concomitant liver disease


• Few studies have evaluated what is the most effective therapy for DM in cirrhotic patients and what is the impact of treatment of DM on the clinical course of liver disease.

• The treatment of DM of cirrhotic patients has particular characteristics that make it different from type 2 DM without liver disease: (1) About half the patients have malnutrition(2) When clinical DM is diagnosed, the patient has advanced liver

disease(3) Most of the oral hypoglycemic agents are metabolized in the

liver(4) Patients often have episodes of hypoglycemia.

Management of diabetes in patientswith concomitant liver disease1. Lifestyle modification

• The initial treatment of patients suffering from mild to moderate hyperglycemia and compensated liver disease may be a lifestyle change, since at this stage the insulin resistance is a dominant factor.

• This may be compromised by poor nutritional status and general health. More than 50% of patients with severe liver disease are malnourished.

Suzuki A, et al: Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol 43:1060–1066, 2005


1. Lifestyle manifestation

• Low-glycemic, low-calorie diets with a weight loss of

1–2 kg/week 1–2 kg/week seem reasonable.

• Physical exercise which improves insulin resistance

may not be an appropriate measure in patients with

active liver disease.


2. Pharmacologic therapy:

• While there are theoretical concerns about

altered drug metabolism and hepatotoxicity,

only patients with evidence of liver failureonly patients with evidence of liver failure

such as ascites, coagulopathy, or

encephalopathy have altered drug

metabolism.


A. Metformin:

• 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 drinkers because it may predispose to lactic acidosis.

• Metformin has not been reported to cause hepatotoxicity and has shown some benefit in patients with NAFLD.

Nair S, et al: Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 20:23–28, 2004


B. Insulin secretagogues:

• 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, may have a reduced ability to counteract hypoglycemia, and thus, the response to therapy should be monitored closely.

Management of diabetes in patientswith concomitant liver diseaseB. Insulin secretagogues:

Clinical trials assessing the efficacy of meglitinides in the treatment of patients with liver disease have not been reported. The pharmacokinetics and tolerability of nateglinide in patients with cirrhosis is not significantly different than in control subjects. Repaglinide and nateglinide have not been associated with hepatotoxicity.


C. 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.

• There was also a reduction in blood ammonia levels, which paralleled an increase in bowel movement frequency.


C. α-Glucosidase inhibitors:

It was speculated that the increased bowel frequency favored the proliferation of saccharolytic bacteria while reducing the proliferation of proteolytic bacteria, resulting in a reduction in intestinal ammonia production.

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.

Gentile S, et al: A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 3:184 –191, 2005


D. Thiazolidinediones (TZD):• TZDs may be especially useful because they enhance

insulin sensitivity, the underlying defect in NAFLD.

• There has been concern about their potential hepatotoxicity because of the experience with troglitazone.

• However, 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%).

Harrison S, et al: A double-blind, placebo-controlled trial of pioglitazone in the treatment of non-alcoholic steatohepatitis (NASH). Gastroenterology 128 (Suppl 2):A681, 2005


D. Thiazolidinediones (TZD):

• 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 .

• Monitoring is recommended periodically thereafter as clinically indicated rather than every 2 months as previously recommended.


E. Insulin:

• Insulin treatment is frequently required in patients with diabetes and liver disease. Insulin requirements, however, may vary.

• 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.

• In patients with hepatic encephalopathy who require high-carbohydrate diets, resulting in postprandial hyperglycemia, rapid-acting insulin analogs may be particularly useful.

MANAGEMENT OF LIVER DISEASE IN MANAGEMENT OF LIVER DISEASE IN PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES


I. Abnormal liver function tests:

• All patients with type 2 diabetes should have an ALT and AST test done as part of their initial evaluation.

• At least 95% of patients with a confirmed minor elevation of ALT or AST have chronic liver disease independent of the degree of elevation. Thus, it is always necessary to obtain a specific diagnosis.

• The most likely etiologies of minor elevations of ALT/AST are NAFLD, hepatitis C, hepatitis B, and alcohol.

MANAGEMENT OF LIVER DISEASE IN MANAGEMENT OF LIVER DISEASE IN PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETESII. Fatty liver disease The diagnosis of NAFLD or NASH should be

suspected in any patient with type 2 diabetes, especially if there are abnormal liver function tests. It should be specifically looked for in all obese patients with type 2 diabetes.

Ultrasound studies may reveal a diffuse increase in echogenicity, so-called “bright” liver.

Most patients with NAFLD found incidentally or by screening ultrasound have a normal ALT.


Treatment of NAFLD: Most patients do not need to be treated. Only

patients with biopsy-proved NASH or the risk factors (reversed ALT/AST ratio, hypertriglyceridemia & thrombocytopenia) should be treated.

The treatment consists of measures to lose weight as well as pharmacologic intervention.

MANAGEMENT OF LIVER DISEASE IN MANAGEMENT OF LIVER DISEASE IN PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETESTreatment of NAFLD:

1. Exercise and weight reduction: Weight loss and exercise, which enhance insulin

sensitivity and result in reduction of steatosis. Rapid weight reduction, however, may increase necrosis,

inflammation, and fibrosis. The ideal rate of weight loss is not known, but 1.5

kg/week has been recommended. Recent studies have demonstrated that bariatric surgery

either improves or completely reverses steatosis in patients with obesity with or without DM.

MANAGEMENT OF LIVER DISEASE IN MANAGEMENT OF LIVER DISEASE IN PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETESTreatment of NAFLD:

2. Pharmacologic therapy Pharmacologic therapy of NAFLD is evolving. While

many studies have shown improvement in steatosis. There are neither long-term studies to determine whether they alter the natural history of the disease nor studies to indicate whether relapse occurs after treatment withdrawal.

Gemfibrozil, vitamin E, metformin, betaine, silymarine, pioglitazone, rosiglitazone, atorvastatin, losartan, orlistat, and pentoxifylline have all been tried and have all been shown in small trials to improve liver enzymes.


Pharmacologic therapy of NAFLD: Given that insulin resistance is central to the

pathogenesis of NAFLD, insulin sensitizing agents should have utility, and there is increasing evidence that they do.

Metformin has shown mixed results in human trials with some improvement in ALT but not in histology. At this time, treatment with metformin is not recommended outside of clinical trials.

Five studies using pioglitazone from 16 to 48 weeks have been published. All have shown improvement in serum ALT and most in histology.

Lutchman G, et al: Changes in serum adipokine levels during pioglitazone treatment for nonalcoholic steatohepatitis: relationship to histological improvement. Clin Gastroenterol Hepatol 4: 1048–1052, 2006

MANAGEMENT OF LIVER DISEASE IN MANAGEMENT OF LIVER DISEASE IN PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETESPharmacologic therapy of NAFLD:

Three prospective controlled studies using

ursodeoxycholic acid, which reduces apoptosis and

has cytoprotective properties, have been conducted.

The results have been mixed.

Statins may reduce hepatic fat content in patients with

hyperlipidemia and NASH.

Lindor K: Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized, placebo-controlled study (Abstract). Gastroenterology 124 (Suppl.1):A336, 2003

Horlander J, Kwo P, Cummings O: Atorvastatin for the treatment of NASH. Gastroenterology 5:A-544 , 2001


Pharmacologic therapy of NAFLD: Oxidative stress has been shown to be important in the

pathogenesis of NASH. It seems reasonable, therefore, to try therapy with antioxidants.

Pilot studies with vitamin E have been conducted with promising results, but a meta-analysis of high-dose vitamin E revealed an increase in overall mortality.

Pentoxifylline is a compound that inhibits TNF-α. It is used in the treatment of alcoholic hepatitis. A pilot study has shown improvement in liver enzymes in patients with NASH. However, the high incidence of side effects led to early withdrawal in many patients.Miller ER, 3rd, et al: Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37– 46, 2005

Current Pharmacological Options for ttt of NAFLD: ADA scientific sessions 2014Medication Results OutcomeGlucose lowering agentsMetformin Mixed results AST/ALT,,MRS,,Histology

piogltazone Effective Histology

Exenatide Effective(NAFLD) AST/ALT,,,MRS

Liraguide Effective(NAFLD) AST/ALT,,,CT

Lipid lowering agents

Statin Ineffective AST/ALT,,,Histology

Niacin Ineffective AST/ALT,,MRS

Fibrates Ineffective AST/ALT,,MRS

Orlistate Ineffective Histology

Vitamin E Mixed results AST/ALT,,,Histolog

Ursodesoxycholic acid Mixed results AST/ALT,,,Histology

Pentoxyfyllin Effective AST/ALT,,,Histology

Medical History and physical exam

AST/ALT

Liver ultrasoundAssess risk of

NAFLDNo farther evaluation

Consider liver ultrasound in

selected cases

Assess risk of NAFLD

Contemplate alternative diagnostic tools (clinical models biomarkers, alternative imaging

tests, etc.

Consider biopsy

Recommend hepatology referral to rule out other

cases of liver diseases

• Close flowing up • Address lifestyle and

cv risk factorsNASHNo NASH

• Lifestyle intervention• Consider pharmacological therapy

AbnormalNormalRule out other causes of liver disease

Low riskHigh risk

NormalNAFLD

High risk

Low risk

NAFLD

Normal

Algorithm for the Management of NAFLD by Endocrinologistic

RecommendHepatology referral

Family historyT2DM ? Obesity?MetabolicElevated

SummarySummary Type 2 diabetes is associated with a large number of liver

disorders including elevated liver enzymes, fatty liver disease, cirrhosis, hepatocellular carcinoma. In addition, there is an unexplained association with HCV.

The presence of liver disease (unless decompensated) has little implication for the specific treatment of diabetes, and the presence of diabetes has little implication for the specific treatment of liver disease.

Patients with decompensated liver disease are more susceptible to hypoglycemia and require careful monitoring.

There continues to be a need for long-term placebo controlled trials for the treatment of NAFLD and for the treatment of diabetes in patients with liver disease.

Dm & liver

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