Diabetes Mellitus

Diabetes Mellitus

Definition

Is a multifactorial disorder caused by diminished insulin action due to its decreased availability or effectiveness in varying combinations.

Types of diabetes:

(based on aetiology)

Type 1: immune mediated or idiopathic

Type 2: insulin resistance /insulin deficiency

Type 3:

• · genetic syndromes
• · drug induced
• · hormonal
• · malnutrition related etc.

Type 4: gestational diabetes

Diagnosis

With symptoms:

A random blood sugar of >11.1mmol/l (200mg/dl) is diagnostic

Without symptoms:

· WHO (1985)

FBS 2hr PGBS

= or> 7.8mmol/l and/or =or>11.1 mmol/

(140mg/dl) (200mg/dl)

(IGT :FBS <7.8 and PGBS 7.8-11.1)

· ADA (1997)

FBS= or> 7mmol/l

(126mg/dl)

(IFG: 6.1 - 6.9 mmol/l)

WHO (1999)

FBS = or>7mmol/l

(IGT:7-11.1mol/l)

Presentations:

(1) Routine examination

(2) Clinical symptoms:

· Thirst Pruritus vulvae

· Polyuria Balanitis

· Polydipsia Impotence

· Nocturia Changes in vision

· Wt. Loss Parasthesiae

· Tiredness

(3) Ketoacidosis

(4) Symptoms of complications

a) Nephropathy Nodular glomerulo sclerosis

(Kimmelsteil Wilson ) NS

CRF

Proteinuria

Gen. Arteriosclerosis

Pyelonephritis

Symptoms of anaemia

Uraemia

N.S.

b) Retinopathy

I. Simple or background microaneurysms

Blot.hges

Exudates

Cotton wool

Tortuous veins

2. Proliferative retinopathy neovascularization

vitreous haemorrhages

3. Exudative retinopathy macular oedema

macular exudates

Cataract – snow flake in Type I

Accltd. Senile in Type 2

c) Macroangiopathy:

Atheroma in large and medium sized blood vessles

CVD

IHD

PVD

c) Macroangiopathy:

Atheroma in large and medium sized blood vessles

CVD

IHD

PVD

d) Neuropathy:

a. Peripheral neuropathy:

Sensory

Motomotor

? mixed

(Charkot’s neuroarthropathy)

b. Aut. Neuropathy, post. Hypotension

Impotence

Bladder retention

Bowel diarrhoea

Gust sweating

c. Mononeuropathy CTS

Lat.pop

Cervical sp.root

TI

e. Dermopathy: Carbuncles

ulcers

muco cutaneous candidiasis

EVALUATION OF A DIABETIC PATIENT

First visit

History

• History

• SYMPTOMS OF DIABETES

polyuria, nocturia, polydipsia polyphagia, recent weight loss or weight gain, tingling, numbness or pain in the hands and or feet (night cramps), pruritus, vaginal discharge, balanitis.

• DIABETIC HISTORY

Age at which diabetes was detected, duration of disease, family history, previous and current treatment

Drug history (steroids)

• PAST HISTORY

HT, Hyperlipidaemia, IHD, stroke, PVD, liver disease,erectile dysfunction.

Smoking, alcohol history, 24 hour dietary recall

EXAMINATION

Anthropometric measures

• Height
• Weight
• Body mass index- Weight in kg / (Height in m)2
• Waist circumference

Detailed examination

• Including signs of insulin resistance like acanthosis nigricans, skin tags
• Signs of Hyperlipidaemia e.g.: xanthelasma, xanthomas.
• Pay particular attention to cardiovascular system, check blood pressure

• Foot examination

• a must in every diabetic patient – skin, nails, hair, temp, pulses.

• Dilated fundoscopy

EVALUATION OF A DIABETIC PATIENT
First visit

• What type?

• Are there complications?

• Any underlying cause?

• Risk factors of CAD?

Features of Type 1 diabetes

• Early onset

• Children/young adults

• Generally thin

• Not responding to OHAs

• C-peptides

Features of Type 2 diabetes

• Family history present

• Obese or nonobese

• Middle aged or elderly

• Features of metabolic syndrome

Visceral Fat

Features of Type 3 diabetes

· Iatrogenic

· Endocrine

· Malnutrition

· Pancreatic Diabetes

· Genetic syndromes

Are there complications

· Retinopathy

· Nephropathy

· IHD

· CVD

· PVD

· Skin

· Foot

Nephropathy

· Hypertension

· Proteinuria

· Retinopathy

Ischaemic heart disease

· History

· Hypertension

· Peripheral pulses

· Carotid bruits

· ECG

· Xanthomas

Cerebrovascular disease

· History

· Carotid bruits

Peripheral Vascular Disease

· Peripheral pulses

· Vasomotor changes

· Ulcers

Skin

· Dermopathy

· Ulcers

· Cellulitis

· Necrobiosis diabeticorum

· Mycoses

· Gangrene

Foot

· Curvatures

· Deformities

· Ulceration

· Callosities

· Fissuring

Investigations

– FBS and PPBS

– HbA1C

– Fasting lipid profile

– Blood urea and electrolytes

– Urine analysis: Ketones, protein, glucose

– Urine Microalbumin-

– ALT, AST, ALP

– ECG

– Islet cell antibody/GAD antibody if considering type 1 diabetes

Treatment

To allow the patient to lead a comfortable normal life and to prevent complications

3 methods of treatment:

1. Diet alone 60%

2. Diet and oral hypo. Agts. 20%

3. Diet and insulin 20%

Choice of therapeutic regimes

1. Type I <40 most will need insulin

2. >40 specially obese ones could be controlled on diet alone

3. >40 who fail with diet.

§ Non obese: sulphonylureas

§ Obese: biguanides

Failure: may need insulin

Diet Principles:

a. Total cal. Requirement age, sex, occupation

Actual weight in relation to ideal weight

Economic status

b. Proportion of cals from CHO 60 (instd.of 46%)

Prts 15 (……….. 12%)

Fats 25 (………. 42%)

c. Local availability and preference

d. Foods well spread through out the day

e. Foods should be of high fibre content (slowly digested and absorped)

Oral hypoglycaemic agents

a. Sulphonylureas act by sensitising beta cell to the action of glucose

increase insulin receptors.

Eg. Chlorpropamide

Tolbutamide

Glibenclamide

Glipizide

b. Biguanides . act by reducing hepatic gluconeogenesis

Increasing peripheral utilisation of glucose

Useful in obese diabetics

Danger of lactic acidosis with phenformin

C.Others:repaglinide,acarbose,troglitazone

Oral hypoglycaemic agents

a. Sulphonylureas act by sensitising beta cell to the action of glucose

increase insulin receptors.

Eg.

· Chlorpropamide

· Tolbutamide

· Glibenclamide

· Glipizide

b. Biguanides . act by reducing hepatic gluconeogenesis

Increasing peripheral utilisation of glucose

Useful in obese diabetics

Danger of lactic acidosis with phenformin

C.Others:repaglinide,acarbose,troglitazone

Insulins

Indications:

a. Type I diabetes

b. Type 2 where maximum doses of OHA have failed(sec.OHA failure)-

c. Type 2 younger patients to prevent tissue damage

d. With complications (specially young pts)

Infections

Ketoacidosis

Neuropathy

Foot lesions

e. pregancy

f. glucose toxicity

Types of insulins

Species: purity: Duration:

Bovine conventional Short

Porcine single peak intermediate

Human highly purified long

Rapid-Acting Insulin

• Lispro (Humalog)

• Insulin Aspart (Novorapid)

• These are used as bolus (mealtime) insulin

Short-Acting Insulin

• Regular insulin (Actrapid /Humlin R)

• Short-acting

• Onset of action 30-60 minutes

• Duration of action 5-8 hours.

• To be taken 20-30 minutes before meals.

Intermediate-Acting Insulin

• NPH (Insulatard/ Humulin N) & Lente

• Their appearance is cloudy

• Onset of action is about 2 hours after injection

• Peak effect is from 6-10 hours

Long-Acting Insulin

• Detemir (Levemir)

• Glargine (Lantus)

– peakless delivery over 24 hours.

– Clear in solution

– Cannot be mixed with other insulin

– Usually given at bedtime.

– Lower fasting glucose levels and less hypoglycemia

Pre-Mixed Insulin

• 70/30 means 70% NPH and 30% Regular

• 50/50 means 50% NPH and 50% regular

• Addition of protamine to lispro: used in 75/25 combinations

• Protamine to aspart: 70/30 combination (Novomix 30)

Administration:

1. Low dose frequent

2. Sliding scale

3. According to previous blood sugar estimation

Comas in diabetes

1. Hyperglycaemic : Keto acidotic

Non keto acidotic

2. Hypoglycaemic

3. Other metabolic comas:

sec. to diabetes uraemia

Lactic acidosis

4. Other independent causes ex. SAH

Ketoacidosis

Pathogenesis: Pptd by infections

Trauma

Drugs

Non compliance

Clinical: Air hunger Anorexia

Dehydration vomiting

Ketone smell Abd. Pain

Wt loss Low BP

Fatigue

Non ketotic. Usually in elderly

Only dehydration is present

Investigations:

Blood sugar HCO3

Urea PCV

Na, K UFR

pH ECG

Hb

Treatment:

a) Fluids, N. Saline

I lit. first 1/2 hr

I lit next hour

I lit next 2 hrs

Then 500 ml hrly total of 5l.Change to 5% dext. when blood sugar is 10-16 mmol.alternating with N saline

b)Insulin: Sol. Insulin 20 units IV

10 units IM hrly till blood sugar is 13mmol.

Then 10 units SC 4 hrly

c)Potassium: add I.gm(20mmol) to each L of fluid Beginning with second L of N saline

Omit K if S.K is over 6 mmol.

d) HCO₃, 100mmol of NaHCO₃ if pH is below 7.1 Ppt. In 1 to 1 1/2 hrs if pH is still less than 7.1

e) Gen. Management:

Monitor pulse, BP, CVP urine output.

NG suction

Oxygen

Catheterise bladder

Monitor blood sugar, electrolytes, urea, pH

HCO₃ 4 hrly

Ppting treat , cause

Mangement of unconcious state

DIC

Hypoglycaemia

Hypo Hyper

by inc. insulin Infection

starvation stress

Exercise Non compliance

Onset: sudden gradual

Clinical:

Drowsy Drowsy

Pupils dilated Normal size

Bounding pulse Low vol. Pulse

BP n. or inc. sys Normal or low

Hydration normal Dehydarated

Breathing normal acidotic

Urine output normal reduced

Fits fits unusual

Abn. Behavior Abn. Behaviour unusual

Lab, Low BS, pH, HCO₃, BU

CHRONIC MYELOID LEUKAEMIA

Leukaemias

What are Leukemias

Neoplasm of white blood cell and its precursor

Clonal proliferations and accumulation of cells in marrow

Classify as

· Acute leukaemias

· Chronic leukaemias

Types of Leukaemia

Introduction- CML

· Clonal malignant myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate

· Results in increases in myeloid cells, erythroid cells and platelets in peripheral blood and marked myeloid hyperplasia in the bone marrow

· Originate in a single abnormal haemopoietic stem cell

· Incidence :1 per 100,000 (UK)

· Accounts for 7-15% of all leukaemia in adults

· Median age : 53 years

· All age groups, including children, can be affected

Etiology

· Not clear

· Little evidence of genetic factors linked to the disease

· Increased incidence

o Survivors of the atomic disasters at Nagasaki & Hiroshima

o Post radiation therapy

Leukaemogenesis

· Philadelphia chromosome is an acquired cytogenetic anomaly that is characterizes in all leukaemic cells in CML

· 90-95% of CML pts have Ph chromosome

· Reciprocal translocation of chromosome 22 and chromosome 9

· BCR (breakpoint cluster region) gene on chromosome 22 fused to the ABL (Ableson leukemia virus) gene on chromosome 9

· Ph chromosome is found on myeloid, monocytic, erythroid, megakaryocytic, B-cells and sometimes T-cell proof that CML derived from pluripotent stem cell

· Molecular consequence of the t(9;22) is the fusion protein BCR–ABL, which has increased in tyrosine kinase activity

· BCR-ABL protein transform hematopoietic cells so that their growth and survival become independent of cytokines

· It protects hematopoietic cells from programmed cell death (apoptosis)

Clinical Features

o Disease is biphasic, sometimes triphasic

o 40% asymptomatic

o Chronic phase

o Splenomegaly often massive

o Symptoms related to hypermetabolism

o Weight loss

o Anorexia

o Lassitude

o Night sweats

o Features of anaemia

o Pallor, dyspnoea, tachycardia

o Abnormal platelet function

o Bruising, epistaxis, menorrhagia

o Hyperleukocytosis

o thrombosis

o Increased purine breakdown : gout

o Visual disturbances

o Priapism

o Lab features

o Peripheral blood film

o Anaemia

o Leukocytosis (usu >25 x 10⁹/L, freq> 100 x 10⁹/L

o WBC differential shows granulocytes in all stages of maturation

o Basophilia

o thrombocytosis

o Bone marrow

o Hypercellular (reduced fat spaces)

o Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1)

o Myelocyte predominant cell, blasts less 10%

o Megakaryocytes increased & dysplastic

o Increase reticulin fibrosis in 30-40%

o Other lab features :

o NAP reduced

o Serum B12 and transcobalamin increased

o Serum uric acid increased

o Lactate dehydrogenase increased

o Cytogenetic : Philadelphia chromosome

Laboratory- summary

Lab investigation to confirm diagnosis

Full blood picture

Neutrophil alkaline phosphatase

Bone marrow cytogenetic

Phases

Accelerated phase

Median duration is 3.5 – 5 yrs before evolving to more aggressive phases

Clinical features

Increasing splenomegaly refractory to chemo

Increasing chemotherapy requirement

Lab features

Blasts>15% in blood

Blast & promyelocyte > 30% in blood

Basophil 20% in blood

Thrombocytopenia

Cytogenetic: clonal evolution

Phases

Blastic phase

Resembles acute leukaemia

Diagnosis requires > 30% blast in marrow

2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic phase

Survival : 9 mos vs 3 mos (lym vs myeloid)

General Management

o Discussion with family

o The disease & diagnosis

o Prognosis

o Choices of treatment

§ Cytotoxic drug vs bone marrow transplant

§ Side effect

o CML - principles of treatment

o Relieve symptoms of hyperleukocytosis, splenomegaly and thrombocytosis

o Hydration

o Chemotherapy (bulsuphan, Hydoxyurea)

o Control and prolong chronic phase (non-curative)

o alpha interferon+chemotherapy

o imatinib mesylate

o chemotherapy (hydroxyurea)

o CML - principles of treatment

o Treatment cont…

o Eradicate malignant clone (curative)

o allogeneic transplantation

o alpha interferon ?

o imatinib mesylate/STI 571 ?(Thyrosine kinase inhibitor)

o Chemotherapy

o Busulphan

o Alkylating agent

o Preferred in older pts (not candidate for transplant)

o Side effect :

§ prolonged myelosuppression

§ Pulmonary fibrosis

§ Skin pigmentation

§ infertility

o Chemotherapy

o Hydoxyures

o Fewer side effect

o Acts by inhibiting the enzyme ribonucleotide reductase

o Haematological remissions obtain in 80% for both drugs

o However disease progression not altered and persistence of Ph chromosome containing clone

o Chemotherapy

o Recombinant human α- Interferon

o Prolong chronic phase and increase survival

o Haematogical and cytogenetic remission

o Side effect

§ Flu like symptoms

§ Fever and chills

§ Anorexia

§ Depression

o CML - prognosis

o Median survival 3.5 yrs (range 2-8 yrs)

o Interferon + chemotherapy :6 years

o Transplant : 5+ years

o imatinib mesylate ?