Diabetes Mellitus

Diabetes Mellitus

Definition : Diabetes mellitus is a metabolic disorder characterised by chronic hyperglycemia associated with disturbance of carbohydrate, fat & protein metabolism.

CLASSIFICATION 

1. Type I diabetes mellitus (10 %) : earlier called - Insulin dependent or Juvenile-onset diabetes.

• Type I A diabetes mellitus : Immune mediated
• Type I B diabetes mellitus : Idiopathic causes

2. Type II diabetes mellitus ( 80 % ) : earlier called - Non-insulin dependent or maturity onset diabetes.

3. Gestational or pregnancy induced diabetes mellitus (4 % )

4. Other specific types of diabetes (10 % ) -

• Genetic defect of β-cell function due to mutations in various enzymes. earlier called maturity onset of the young ( hepatocyte nuclear transcription factor, glucokinase).
• Genetic defect in insulin action ( type A insulin resistance).
• Disease of exocrine pancreas (chronic pancreatitis, pancreatic tumours and post-pancreatectomy).
• Endocrinopathies (acromegaly, cushing's syndrome and pheochromocytoma).
• Drug or chemical induced ( steroids, thyroid hormone, thiazides, β-blockers etc.).
• Infections ( congenital rubella, cytomegalovirus).
• Uncommon forms of immune-mediated diabetes mellitus (stiff man syndrome, anti insulin receptor antibodies).
• Other genetic syndrome (Down's syndrome, Klinefelter's syndrome, Tumour's syndrome).

1. TYPE I DIABETES MELLITUS :  It constitutes about 10% of cases of DM. It is characterised by absolute deficiency of insulin secretion caused by pancreatic β-cell destruction, usually resulting from an autoimmune attack.

A. Type I A DM (Immune-mediated) - Characterised by autoimmune destruction of β-cells resulting in insulin deficiency.

B. Type I B DM (Idiopathic) - Characterised by insulin deficiency with tendency to develop ketosis but autoimmune causes are not found.

Contrasting Features Of Type I and Type II Diabetes Mellitus
No.	Features	Type I DM	Type II DM
1.	Frequency	10 – 20 %	80 – 90 %
2.	Age at onset	Below 35 years	After 40 years
3.	Type of onset	Abrupt and severe	Gradual and insidious
4.	Weight	Normal	Obese / non-obese
5.	Family history	< 20%	About 60 %
6.	Genetic locus	Unknown	Chromosome 6
7,	Diabetes in identical twins	50 % chance	80 % chance
8.	Pathogenesis	Autoimmune destruction of ß cells	Insulin resistance, impaired insulin secretion
9.	Islet cell antibodies	Yes	No
10.	Blood insulin level	Decreased insulin	Normal or increased insulin
11.	Islet cell changes	Insulitis, β-cells depletion	No insulitis, later fibrosis of islets
12.	Amyloidosis	Infrequent	Common in chronic cases
13.	Clinical management	Insulin and diet	Diet, exercise, oral drugs, insulin
14.	Acute complications	Ketoacidosis	Hyperosmolar coma

2. TYPE II DIABETES MELLITUS : It constitutes about 80% of cases of DM. It is caused by a relative insulin deficiency  due to combination of peripheral resistance to insulin action and inadequate compensatory response of insulin secretion by the pancreatic β-cells.

Etiology : 

1. Family history of type 2 DM.
2. Obesity.
3. Habitual physical inactivity.
4. Race and ethnicity ( Blacks, Asians, Pacific Islanders).
5. Previous identification of impaired fasting glucose or impaired glucose tolerance.
6. History of gestational DM or delivery of baby heavier than 4 kg.
7. Hypertension.
8. Dyslipidaemia (HDL level <35 mg/dl or triglycerides >250 mg/dl ).
9. Polycystic ovary disease and acanthosis nigricans.
10. History of vascular disease.

3. GESTATIONAL  OR PREGNANCY INDUCED DM : About 4% pregnant women develop DM due to metabolic changes during pregnancy. Although they revert back to normal glycaemia after delivery, these women are prone to develop DM later in their life.

PATHOGENESIS : Hyperglycaemia may develop due to following causes

• Reduced insulin secretion.
• Decrease glucose use by the body.
• Increased glucose production.

Pathogenesis

Pathogenesis of Type I DM : The basic phenomenon  is destruction of β-cells mass, usually leading to absolute insulin deficiency. While Type I B remain idiopathic. So we will discuss about only Type I A DM.

1. Genetic susceptibility –  

• Identical twins are more prone if either one are affected.
• HLA genes (Commonest locus being affected is on chromosome 6p21 ( HLA D) like HLA DR3 / DR4 with DQ8 haplotype. The non HLA genes like that for insulin or polymorphism in CD25 (normally regulated the function of T cells.

2. Autoimmunity – 

• Presence of islet cell antibodies against GAD (glutamic acid decarboxylase), insulin etc.
• Insulitis, it consists of CD8+ T lymphocytes with variable number of CD4+ T lymphocytes and macrophages.
• Selective destruction of ß-cells while other islet cells (alpha cells, delta cells and PP cells)  are unaffected.
• Role of T cells mediated autoimmunity is supported by transfer of the disease from affected animal to healthy animal by infusing T lymphocytes.
• Association with other autoimmune diseases 10-20% cases like Grave’s disease, Addison’s disease, Hashimoto’s thyroiditis, pernicious anaemia.

3. Environmental factors – 

• Certain viral infection preceding the onset of disease like mumps, measles, coxsackie B virus, cytomegalovirus and infectious mononucleosis.
• Experimental induction with certain chemicals may cause like alloxan, streptozotocin and pentamidine.
• Geographic and seasonal variations.
• Bovine milk protein may also cause. 

Key Points of Pathogenesis of Type I A DM

1. At birth, individual with genetic susceptibility to this disorder have normal ß-cell mass

2. ß-cell act as autoantigens and activate CD4 T lypmhocytes, bringing about immune destruction of pancreatic ß-cells by autoimmune phenomena and tackes months to years. Clinical features of diabetes manifest after  more  than 80% of ß-cell mass has been destroyed.

3. The trigger for autoimmune process appears to be some infectious or environmental factor which specially targets ß-cells.

CLINICAL FEATURES

No.	Features	Type-I DM	Type-II DM
1.	Age	Below 35 years.	Above 40 years.
2.	Onset of symptoms	Abrupt.	Slow and Insidious.
3.	Presentation	Polyuria, polydipsia and polyphagia.	Generally asymptomatic. Polyuria and polydipsia may be present.
4.	Weight	Progressive loss of weight.	Unexplained weakness and loss of weight.
5.	Obesity	Generally absent	Present.
6.	Metabolic complication	Common (Ketoacidosis, hypoglycaemia)	Infrequent (Ketoacidosis)

Sign & Symptoms

COMPLICATIONS

Acute metabolic complications -

1. Diabetic Ketoacidosis.
2. Hyperosmolar hyperglycaemic nonketotic coma (HHS).
3. Hypoglycaemia.

Late systemic complications –

1. Atherosclerosis.
2. Diabetic microangiopathy.
3. Diabetic nephropathy.
4. Diabetic neuropathy.
5. Diabetic retinopathy.
6. Infections ( tuberculosis, pneumonia, pyelonephritis, otitis, carbuncles and diabetic ulcers).

Complications

DIAGNOSIS OF DIABETES

1. Urine testing – Glucosuria and ketonuria. 
2. Single Blood Sugar Estimation. 
3. Screening by Fasting Glucose Test.
4. Oral Glucose Tolerance Test etc.

TREATMENT OF DIABETES MELLITUS

Management of type 2 diabetes -

•  Weight loss.
• Healthy eating ( e.g. fewer calories, fewer food containing saturated fats, high fiber containing food etc.). 
• Regular exercise.
• Blood sugar monitoring.
• Diabetes medications and insulin therapy (e.g. metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors and insulin etc.).

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Endocarditis

Endocarditis

Definition : Inflammatory involvement of endocardium of the heart is called endocarditis it may be valvular endocarditis and mural endocarditis.

Classification of Endocarditis –

A. Non-Infective

1. Rheumatic endocarditis.

2. Non-rheumatic endocarditis -

a) Atypical verrucous (Libman-Sacks) endocarditis.

b) Non-bacterial thrombotic (cachectic, marantic) endocarditis.

B. Infective

1. Bacterial endocarditis.

2. Other infective types i.e. tuberculous, syphilitic, fungal, viral and rickettsial.

Infective Endocarditis (vegetations on the valve)

1. RHEUMATIC ENDOCARDITIS – Endocardial lesions of rheumatic fever may involve the valve called rheumatic valvulitis and may involve the mural endocardium called mural endocarditis.

2. NON-RHEUMATIC ENDOCARDITIS –

a) Atypical verrucous (Libman-Sacks) endocarditis – Libman and Sacks, two American physicians, described a form of endocarditis in 1924 that is characterized by sterile, granular, pink and small or medium sized endocardial vegetations on either or both sides of valve leaflets. Mitral and tricuspid valves are involves and shows fibrinoid necrosis. Which are different from the vegetations of rheumatic heart disease and bacterial endocarditis.

b) Non-bacterial thrombotic (cachectic, marantic) endocarditis – It is the involvement of the heart valves by sterile (do not contain microorganism) thrombotic vegetations. It is commonly seen with debilitating diseases. Embolic phenomenon is seen in many cases that cause infarcts in the brain, lungs, spleen and kidneys. The bland vegetations on infection may produce bacterial endocarditis.

1. INFECTIVE (BACTERIAL) ENDOCARDITIS – It is the serious infection of the valvular and mural endocardium by microbiologic agent leading to formation of bulky, friable vegetations composed of thrombotic debris and organism with destruction of underlying cardiac tissue. Depending upon the severity of infection bacterial endocarditis is divided into acute endocarditis and subacute endocarditis.

a) Acute bacterial endocarditis (ABE) – It is the fulminant and destructive acute infection of the endocardium by highly virulent bacteria in a previously normal heart and almost invariably runs a rapidly fatal course an period of 2-6 weeks.

b) Subacute bacterial endocarditis or endocarditis lenta ( lenta- slow) – It is caused by less virulent bacteria in a previously diseased heart and has gradual downhill course in a period of 6 weeks to a few months and sometimes years.

Distinguishing features of ABE and SABE
	Features	ABE	SABE
1.	Duration	<6 weeks	>6 weeks
2.	Most common organism	Staphylococcus aureus, ß-streptococci	Streptococcus viridans
3.	Virulence of organism	High	Less
4.	Previous condition of valves	Usually previously normal	Usually previously damaged
5.	Lesion on valves	Invasive, destructive, Suppurative	Usually absent
6.	Clinical features	Features of acute systemic infection	Splenomegaly, clubbing of fingers, petechiae

Incidence - Bacterial endocarditis may occur at any age but most common in above 50 years of age persons. Males are more affected than female.

Etiology –

I. Infective agents - About 90% cases of bacterial endocarditis are caused by streptococci and staphylococci.

• In ABE – Staphylococcus aureus (common) and other less common are Pneumococci, Gonococci, ß-streptococci and Enterococci.
• In SABE – Streptococcus viridans (common) and other less common are Streptococcus bovis (normal inhibitant of GIT), Streptococcus pneumonia, Staphylococcus epidermidis (commensal of the skin), gram-negative (E.coli, Klebsiella, Pseudomonas, Salmonella), Pneumococci, Gononcocci and Haemophilus influenza.

II. Predisposing factors –

1. Bacteraemia, septicaemia and pyaemia –

• Periodontal infections.
• Genitourinary tract infections.
• GIT and biliary tract infections.
• Surgery of the bowel, biliary tract and genitourinary tract.
• Skin infections
• Upper and lower respiratory tract infections
• Cardiac catheterization and surgery.

2. Underlying heart disease –

• Chronic rheumatic valvular disease ( in 50% cases).
• Congenital heart disease (in 20% cases).
• Syphilic aortic valve disease, atherosclerotic valvular disease etc.

3. Impaired host defenses –

• Lymphomas.
• Leukaemias.
• Cytotoxic therapy patient.
• Deficient functions of neutrophils and macrophages.

PATHOGENESIS – Bacteria entered and implanted on the cardiac valves and mural endocardium because they have surface adhesion molecules which mediate their adherence to injured endothelium

• The circulating bacteria are lodged much more frequently on previously damaged valves from disease chiefly RHD, congenital heart disease etc.
• Condition producing haemodynamic stress on the valves are the liable to cause damage to the endothelium, favouring the formation of platelet-fibrin thrombi which get infected from circulating bacteria.
• Occurrence of non-bacterial endocarditis.

Distinguishing features of vegetations in major forms of endocarditis

MORPHOLOGICAL FEATURES – Characteristic pathologic features are the presence of typical vegetations or verrucae on the valve cusps or leaflets, and less often on mural endocardium.

Grossly –

• The lesions are the found commonly on the valves of the left heart, most frequently on the mitral and quite rarely on the valves of the right heart.
• The vegetations of the bacterial endocarditis vary in size form a few millimeters to several centimeters, grey-tawny to greenish, irregular, single or multiple and typically friable. They may appear flat, filiform, fungating or polypoid.
• The vegetations in bacterial endocarditis tend to be bulkier and globular than those of subacute bacterial endocarditis and are located more often on previously normal valves, may cause ulceration or perforation of the underlying valve leaflet or may produce myocardial abscess.

Microscopically – The vegetations of bacterial endocarditis are consists of zones –

• The outer layer or cap consists of eosinophilic material composed of fibrin and platelets.
• Underneath this layer is the basophilic zone containing colonies of bacteria.
• The deeper zone consists of non-specific inflammatory reactions in the cusp itself, and in the case of subacute bacterial endocarditis there may be evidence of repair.

A. Infective endocarditis. B Microscopic structure of vegetations of BE 

COMPLICATIONS – The acute form of bacterial endocarditis is characterized by high grade fever, chills, weakness and malaise. While the subacute form of the disease has non-specific manifestations like slight fever, fatigue, loss of weight and flu like symptoms.

1. Cardiac complications –

a. Valvular stenosis or insufficiency.

b. Perforation, rupture and aneurysm of valve leaflets.

c. Abscess in the valve ring.

d. Myocardial abscess.

e. Suppurative pericarditis.

f. Cardiac failure from one or more of the foregoing complications.

2. Extracardiac complications – Since the vegetations in bacterial endocarditis are typically friable, they tend to get dislodged due to rapid stream of blood and give rise to embolism.

a. Emboli originating from the left side of the heart and entering the systemic circulation affects organ like the spleen, kidneys and brain causing infarcts, abscesses and mycotic aneurysm,

b. Emboli from right side of the heart produce pulmonary abscess.

c. Petechiae ( seen in skin and conjunctiva due to embolism).

d. In subacute bacterial endocarditis, there are painful tender nodules on the finger tips of hands and feet called Osler’s nodes, while in acute bacterial endocarditis, there is appearance of painless, non-tender subcutaneous maculopapular lesions on the pulp of the fingers called Janeway’s spots.

e. Focal necrotising glomerulonephritis is seen more commonly in subacute bacterial endocarditis than in acute bacterial endocarditis.

2. OTHER INFECTIVE TYPES – Besides bacterial endocarditis, various other microbes may occasionally cause infective endocarditis which are named according to the etiologic agents –

A. Tuberculous endocarditis – It’s causative organism is tubercle bacilli. It separate from the bacterial endocarditis due to specific granulomatous inflammation found in tuberculosis. It is characterised by presence of typical tubercles on the valvular as well as mural endocardium and may form tuberculous thromboemboli.

B. Syphilitic endocarditis – The severest manifestation of cardiovascular syphilis is aortic valvular incompetence.

C. Fungal endocarditis – Rarely, endocardium may be infected with fungi such as from Candida albicans, Histoplasma capsulatum, Aspergillus, Mucor, Coccidiodomycosis, Cryptococcosis, Blastomycosis and Actinomycosis. Opportunistic fungal infections like candidiasis and aspergillosis are seen more commonly in patient receiving long term antibiotic therapy, intravenous drugs abusers and after prosthetic valve replacement. Fungal endocarditis produces an appearance similar to that in bacterial endocarditis but the vegetations are bulkier in fungal endocarditis.

D. Viral endocarditis – There is only experimental evidence of existence of this entity.

E. Rickettsial endocarditis – Another rare cause of endocarditis is from infection with rickettsiae in Q fever.

Diagnosis - Blood tests, Echocardiogram, ECG, Chest X-ray, CT scan and MRI.

Treatment - The main treatment is antibiotics, sometime surgery is required.

• Medications - Antibiotics and Penicillin
• Surgery - Valve replacement.

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